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Postnatal growth retardation

MedGen UID:
395343
Concept ID:
C1859778
Finding
Synonyms: Growth failure, postnatal; Growth retardation as children; Growth retardation, postnatal; Postnatal growth deficiency; Postnatal growth failure
 
HPO: HP:0008897

Definition

Slow or limited growth after birth. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • Postnatal growth retardation

Conditions with this feature

Bloom syndrome
MedGen UID:
2685
Concept ID:
C0005859
Disease or Syndrome
Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. Despite their very small head circumference, most affected individuals have normal intellectual ability. Women may be fertile but often have early menopause, and men tend to be infertile, with only one confirmed case of paternity. Serious medical complications that are more common than in the general population and that also appear at unusually early ages include chronic obstructive pulmonary disease, diabetes mellitus as a result of insulin resistance, and cancer of a wide variety of types and anatomic sites.
Glycogen storage disease, type VI
MedGen UID:
6643
Concept ID:
C0017925
Disease or Syndrome
Glycogen storage disease type VI (GSD VI) is a disorder of glycogenolysis caused by deficiency of hepatic glycogen phosphorylase. This critical enzyme catalyzes the rate-limiting step in glycogen degradation, and deficiency of the enzyme in the untreated child is characterized by hepatomegaly, poor growth, ketotic hypoglycemia, elevated hepatic transaminases, hyperlipidemia, and low prealbumin level. GSD VI is usually a relatively mild disorder that presents in infancy and childhood; rare cases of more severe disease manifesting with recurrent hypoglycemia and marked hepatomegaly have been described. More common complications in the setting of suboptimal metabolic control include short stature, delayed puberty, osteopenia, and osteoporosis. Hepatic fibrosis commonly develops in GSD VI, but cirrhosis and hypertrophic cardiomyopathy are rare. Clinical and biochemical abnormalities may decrease with age, but ketosis and hypoglycemia can continue to occur.
Mucopolysaccharidosis type 7
MedGen UID:
43108
Concept ID:
C0085132
Disease or Syndrome
Mucopolysaccharidosis type VII is an autosomal recessive lysosomal storage disease characterized by the inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (Shipley et al., 1993). MPS VII was the first autosomal mucopolysaccharidosis for which chromosomal assignment was achieved.
Dubowitz syndrome
MedGen UID:
59797
Concept ID:
C0175691
Disease or Syndrome
Dubowitz syndrome (DS) is a rare multiple congenital syndrome characterized primarly by growth retardation, microcephaly, distinctive facial dysmorphism, cutaneous eczema, a mild to severe intellectual deficit and genital abnormalities.
Aicardi syndrome
MedGen UID:
61236
Concept ID:
C0175713
Disease or Syndrome
Aicardi syndrome is a neurodevelopmental disorder that affects primarily females. Initially it was characterized by a typical triad of agenesis of the corpus callosum, central chorioretinal lacunae, and infantile spasms. As more affected individuals have been ascertained, it has become clear that not all affected girls have all three features of the classic triad and that other neurologic and systemic defects are common, including other brain malformations, optic nerve abnormalities, other seizure types, intellectual disability of varying severity, and scoliosis.
Freeman-Sheldon syndrome
MedGen UID:
120516
Concept ID:
C0265224
Disease or Syndrome
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Schinzel-Giedion syndrome
MedGen UID:
120517
Concept ID:
C0265227
Disease or Syndrome
Schinzel-Giedion syndrome is a highly recognizable syndrome characterized by severe mental retardation, distinctive facial features, and multiple congenital malformations including skeletal abnormalities, genitourinary and renal malformations, and cardiac defects, as well as a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia (summary by Hoischen et al., 2010).
Miller syndrome
MedGen UID:
120522
Concept ID:
C0265257
Disease or Syndrome
Miller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (summary by Ng et al., 2010).
Dyggve-Melchior-Clausen syndrome
MedGen UID:
120527
Concept ID:
C0265286
Disease or Syndrome
Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests (summary by El Ghouzzi et al., 2003).
Cerebro-costo-mandibular syndrome
MedGen UID:
120537
Concept ID:
C0265342
Disease or Syndrome
Cerebrocostomandibular syndrome (CCMS) is characterized mainly by severe micrognathia, rib defects, and mental retardation. A spectrum of rib gap defects have been reported ranging from a few dorsal rib segments to complete absence of ossification. In about half of the 65 reported cases to date, there is cerebral involvement including mental retardation, microcephaly, and histologic anomalies. Both autosomal dominant and autosomal recessive forms of the disorder have been described (Zeevaert et al., 2009). See CDG2G (611209) for a cerebrocostomandibular-like syndrome.
Leprechaunism syndrome
MedGen UID:
82708
Concept ID:
C0265344
Disease or Syndrome
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
CHARGE association
MedGen UID:
75567
Concept ID:
C0265354
Disease or Syndrome
CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. Despite these complications, the life expectancy for many individuals can be normal.
Arginase deficiency
MedGen UID:
78688
Concept ID:
C0268548
Disease or Syndrome
Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms.
Chondrodysplasia punctata 2 X-linked dominant
MedGen UID:
79381
Concept ID:
C0282102
Disease or Syndrome
The findings in X-linked chondrodysplasia punctata 2 (CDPX2) range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including females with no recognizable physical abnormalities. At least 95% of live-born individuals with CDPX2 are female. Characteristic features include growth deficiency; distinctive craniofacial appearance; chondrodysplasia punctata (stippling of the epiphyses of the long bones, vertebrae, trachea, and distal ends of the ribs); often asymmetric rhizomelic shortening of limbs; scoliosis; linear or blotchy scaling ichthyosis in the newborn; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma); coarse hair with scarring alopecia; and cataracts.
Branchiooculofacial syndrome
MedGen UID:
91261
Concept ID:
C0376524
Disease or Syndrome
The branchiooculofacial syndrome (BOFS) is characterized by: branchial (cervical or infra- or supra-auricular) skin defects that range from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; ocular anomalies that can include microphthalmia, anophthalmia, coloboma, and nasolacrimal duct stenosis/atresia; and facial anomalies that can include ocular hypertelorism or telecanthus, broad nasal tip, upslanted palpebral fissures, cleft lip or prominent philtral pillars that give the appearance of a repaired cleft lip (formerly called "pseudocleft lip") with or without cleft palate, upper lip pits, and lower facial weakness (asymmetric crying face or partial 7th cranial nerve weakness). Malformed and prominent pinnae and hearing loss from inner ear and/or petrous bone anomalies are common. Intellect is usually normal.
Roberts-SC phocomelia syndrome
MedGen UID:
95931
Concept ID:
C0392475
Disease or Syndrome
ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction, limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening), hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, and syndactyly), elbow and knee flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus]), and craniofacial abnormalities (which can include bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, and underdeveloped ala nasi), ear malformation, and corneal opacities. Intellectual disability (ranging from mild to severe) is common. Early mortality is common among severely affected pregnancies and newborns; mildly affected individuals may survive to adulthood.
Microcephalic osteodysplastic primordial dwarfism type II
MedGen UID:
96587
Concept ID:
C0432246
Disease or Syndrome
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities.
Microphthalmia with limb anomalies
MedGen UID:
154638
Concept ID:
C0599973
Disease or Syndrome
Ophthalmo-acromelic syndrome is a condition that results in malformations of the eyes, hands, and feet. The features of this condition are present from birth. The eyes are often absent or severely underdeveloped (anophthalmia), or they may be abnormally small (microphthalmia). Usually both eyes are similarly affected in this condition, but if only one eye is small or missing, the other eye may have a defect such as a gap or split in its structures (coloboma).\n\nThe most common hand and foot malformation seen in ophthalmo-acromelic syndrome is missing fingers or toes (oligodactyly). Other frequent malformations include fingers or toes that are fused together (syndactyly) or extra fingers or toes (polydactyly). These skeletal malformations are often described as acromelic, meaning that they occur in the bones that are away from the center of the body. Additional skeletal abnormalities involving the long bones of the arms and legs or the spinal bones (vertebrae) can also occur. Affected individuals may have distinctive facial features, an opening in the lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate), or intellectual disability.
Cockayne syndrome type 2
MedGen UID:
155487
Concept ID:
C0751038
Disease or Syndrome
Cockayne syndrome (referred to as CS in this GeneReview) spans a continuous phenotypic spectrum that includes: CS type I, the "classic" or "moderate" form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal (COFS) syndrome; CS type III, a milder and later-onset form; COFS syndrome, a fetal form of CS. CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age five years. CS type III is a phenotype in which major clinical features associated with CS only become apparent after age two years; growth and/or cognition exceeds the expectations for CS type I. COFS syndrome is characterized by very severe prenatal developmental anomalies (arthrogryposis and microphthalmia).
3p- syndrome
MedGen UID:
167067
Concept ID:
C0795806
Cell or Molecular Dysfunction
Characteristic features of the distal 3p- syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), preauricular pits, sacral dimple, and gastrointestinal anomalies are variable features. Although intellectual deficits are almost invariably associated with cytogenetically visible 3p deletions, rare patients with a 3p26-p25 deletion and normal intelligence or only mild abnormalities have been described (summary by Shuib et al., 2009).
Recombinant 8 syndrome
MedGen UID:
167070
Concept ID:
C0795822
Disease or Syndrome
Recombinant chromosome 8 syndrome (Rec8 syndrome) is a chromosomal disorder found among individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have impaired intellectual development, congenital heart defects, seizures, a characteristic facial appearance with hypertelorism, thin upper lip, anteverted nares, wide face, and abnormal hair whorl, and other manifestations (Sujansky et al., 1993, summary by Graw et al., 2000).
Filippi syndrome
MedGen UID:
163197
Concept ID:
C0795940
Disease or Syndrome
Filippi syndrome is characterized by short stature, microcephaly, syndactyly, intellectual disability, and facial dysmorphism consisting of bulging forehead, broad and prominent nasal bridge, and diminished alar flare. Common features include cryptorchidism, speech impairment, and clinodactyly of the fifth finger, Some patients exhibit visual disturbances, polydactyly, seizures, and/or ectodermal abnormalities, such as nail hypoplasia, long eyelashes, hirsutism, and microdontia (summary by Hussain et al., 2014).
Kabuki syndrome
MedGen UID:
162897
Concept ID:
C0796004
Congenital Abnormality
Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.
Peters plus syndrome
MedGen UID:
163204
Concept ID:
C0796012
Disease or Syndrome
Peters plus syndrome is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, characteristic facial features, cleft lip/palate, and variable developmental delay / intellectual disability. The most common anterior chamber defect is Peters' anomaly, consisting of central corneal clouding, thinning of the posterior cornea, and iridocorneal adhesions. Cataracts and glaucoma are common. Developmental delay is observed in about 80% of children; intellectual disability can range from mild to severe.
Marden-Walker syndrome
MedGen UID:
163206
Concept ID:
C0796033
Disease or Syndrome
Marden-Walker syndrome (MWKS) is characterized by psychomotor retardation, a mask-like face with blepharophimosis, micrognathia and a high-arched or cleft palate, low-set ears, kyphoscoliosis, and joint contractures. Other features may include Dandy-Walker malformation with hydrocephalus and vertebral abnormalities (summary by Schrander-Stumpel et al., 1993). There are 2 distal arthrogryposis syndromes with features overlapping those of Marden-Walker syndrome that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and distal arthrogryposis type 5 (DA5; 108145), which are distinguished by the presence of cleft palate and ocular abnormalities, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition.
3MC syndrome 1
MedGen UID:
167100
Concept ID:
C0796059
Disease or Syndrome
The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (summary by Rooryck et al., 2011). Genetic Heterogeneity of 3MC Syndrome Also see 3MC syndrome-2 (3MC2; 265050), caused by mutation in the COLEC11 gene (612502), and 3MC syndrome-3 (3MC3; 248340), caused by mutation in the COLEC1 gene (607620).
Acrocallosal syndrome
MedGen UID:
162915
Concept ID:
C0796147
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
3MC syndrome 2
MedGen UID:
167115
Concept ID:
C0796279
Disease or Syndrome
The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (summary by Rooryck et al., 2011). For a discussion of genetic heterogeneity of 3MC syndrome, see 3MC1 (257920).
Deficiency of phosphoserine phosphatase
MedGen UID:
452940
Concept ID:
C1291463
Disease or Syndrome
3-Phosphoserine phosphatase deficiency is an extremely rare form of serine deficiency syndrome (see this term) characterized clinically by congenital microcephaly and severe psychomotor retardation in the single reported case to date, which was associated with Williams syndrome (see this term).
Microcephalic osteodysplastic dysplasia, Saul-Wilson type
MedGen UID:
722057
Concept ID:
C1300285
Disease or Syndrome
Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech and motor) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy. To date, 16 affected individuals have been reported.
Congenital muscular hypertrophy-cerebral syndrome
MedGen UID:
315658
Concept ID:
C1802395
Disease or Syndrome
Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.
Fanconi anemia complementation group N
MedGen UID:
372133
Concept ID:
C1835817
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia complementation group J
MedGen UID:
323015
Concept ID:
C1836860
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome
MedGen UID:
324684
Concept ID:
C1837073
Disease or Syndrome
Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction (summary by Hoover-Fong et al., 2014). Yamamoto et al. (2014) reviewed 16 reported cases of SMDCRD, noting that all affected individuals presented uniform skeletal findings, with rhizomelia and bowed lower limbs observed in the first year of life, whereas retinal dystrophy had a more variable age of onset. There was severe disproportionate short stature, with a final height of less than 100 cm; scoliosis was usually mild. Visual loss was progressive, with stabilization in adolescence.
Growth delay due to insulin-like growth factor type 1 deficiency
MedGen UID:
373337
Concept ID:
C1837475
Disease or Syndrome
Syndrome with the association of intrauterine and postnatal growth retardation, sensorineural deafness and intellectual deficit. The syndrome is extremely rare and only four cases have been reported in the literature so far. Additional clinical features include microcephaly, adiposity, and insulin resistance. Partial gonadal dysfunction and osteoporosis may also be present. Caused by homozygous mutations in the insulin-like growth factor 1 gene (12q22-q24.1). Transmitted as an autosomal recessive trait.
Syndromic X-linked intellectual disability 12
MedGen UID:
333405
Concept ID:
C1839792
Mental or Behavioral Dysfunction
X-linked intellectual disability, Wilson type is characterised by severe intellectual deficit with mutism, epilepsy, growth retardation and recurrent infections. It has been described in three males from three generations of one family. The causative gene has been localised to the 11p region of the X chromosome.
Growth failure, microcephaly, intellectual disability, cataracts, large joint contractures, osteoporosis, cortical dysplasia, and cerebellar atrophy
MedGen UID:
330820
Concept ID:
C1842321
Disease or Syndrome
Oto-palato-digital syndrome, type II
MedGen UID:
337064
Concept ID:
C1844696
Disease or Syndrome
The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.
Catel-Manzke syndrome
MedGen UID:
375536
Concept ID:
C1844887
Disease or Syndrome
Catel-Manzke syndrome is characterized by the Pierre Robin anomaly, which comprises cleft palate, glossoptosis, and micrognathia, and a unique form of bilateral hyperphalangy in which there is an accessory bone inserted between the second metacarpal and its corresponding proximal phalanx, resulting in radial deviation of the index finger (summary by Manzke et al., 2008).
Alpha thalassemia-X-linked intellectual disability syndrome
MedGen UID:
337145
Concept ID:
C1845055
Disease or Syndrome
Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants.
IMAGe syndrome
MedGen UID:
337364
Concept ID:
C1846009
Disease or Syndrome
IMAGe syndrome is an acronym for the major findings of intrauterine growth restriction (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary abnormalities (in males). Findings reported in individuals with a clinical and/or molecular diagnosis include: IUGR; Some type of skeletal abnormality (most commonly delayed bone age and short stature, and occasionally, metaphyseal and epiphyseal dysplasia of varying severity); Adrenal insufficiency often presenting in the first month of life as an adrenal crisis or (rarely) later in childhood with failure to thrive and recurrent vomiting; Genital abnormalities in males (cryptorchidism, micropenis, and hypospadias) but not in females. Hypotonia and developmental delay are reported in some individuals; cognitive outcome appears to be normal in the majority of individuals.
Roifman syndrome
MedGen UID:
375801
Concept ID:
C1846059
Disease or Syndrome
Roifman syndrome is a multisystem disorder characterized by growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy, distinctive facial dysmorphism, and immunodeficiency (summary by de Vries et al., 2006).
Hypotonia-cystinuria syndrome
MedGen UID:
341133
Concept ID:
C1848030
Disease or Syndrome
A rare, genetic disorder of amino acid absorption and transport, characterized by generalized hypotonia at birth, neonatal/infantile failure to thrive (followed by hyperphagia and rapid weight gain in late childhood), cystinuria type 1, nephrolithiasis, growth retardation due to growth hormone deficiency, and minor facial dysmorphism. Dysmorphic features mainly include dolichocephaly and ptosis. Nephrolithiasis occurs at variable ages.
Mosaic variegated aneuploidy syndrome 1
MedGen UID:
338026
Concept ID:
C1850343
Disease or Syndrome
Mosaic variegated aneuploidy (MVA) syndrome is a rare disorder in which some cells in the body have an abnormal number of chromosomes instead of the usual 46 chromosomes, a situation known as aneuploidy. Most commonly, cells have an extra chromosome, which is called trisomy, or are missing a chromosome, which is known as monosomy. In MVA syndrome, some cells are aneuploid and others have the normal number of chromosomes, which is a phenomenon known as mosaicism. Typically, at least one-quarter of cells in affected individuals have an abnormal number of chromosomes. Because the additional or missing chromosomes vary among the abnormal cells, the aneuploidy is described as variegated.\n\nIn MVA syndrome, growth before birth is slow (intrauterine growth restriction). After birth, affected individuals continue to grow at a slow rate and are shorter than average. In addition, they typically have an unusually small head size (microcephaly). Another common feature of MVA syndrome is an increased risk of developing cancer in childhood. Cancers that occur most frequently in affected individuals include a cancer of muscle tissue called rhabdomyosarcoma, a form of kidney cancer known as Wilms tumor, and a cancer of the blood-forming tissue known as leukemia.\n\nThere are at least three types of MVA syndrome, each with a different genetic cause. Type 1 is the most common and displays the classic signs and symptoms described above. Type 2 appears to have slightly different signs and symptoms than type 1, although the small number of affected individuals makes it difficult to define its characteristic features. Individuals with MVA syndrome type 2 grow slowly before and after birth; however, their head size is typically normal. Some people with MVA syndrome type 2 have unusually short arms. Individuals with MVA syndrome type 2 do not seem to have an increased risk of cancer. Another form of MVA syndrome is characterized by a high risk of developing Wilms tumor. Individuals with this form may also have other signs and symptoms typical of MVA syndrome type 1.\n\nLess commonly, people with MVA syndrome have eye abnormalities or distinctive facial features, such as a broad nasal bridge and low-set ears. Some affected individuals have brain abnormalities, the most common of which is called Dandy-Walker malformation. Intellectual disability, seizures, and other health problems can also occur in people with MVA syndrome.
Cerebrooculonasal syndrome
MedGen UID:
340138
Concept ID:
C1854108
Disease or Syndrome
A multisystem malformation syndrome that has been reported in about 10 patients. The clinical features include bilateral anophthalmia, abnormal nares, central nervous system anomalies, and neurodevelopmental delay. Additional features include brachycephaly and other facial anomalies. Non-facial anomalies have also been reported: postaxial polydactyly, genital hypoplasia. All cases reported so far have been sporadic, suggesting that the syndrome may be due to a new dominant mutation.
Mitochondrial myopathy-lactic acidosis-deafness syndrome
MedGen UID:
343245
Concept ID:
C1855033
Disease or Syndrome
A rare metabolic myopathy presenting during childhood, and characterized clinically by growth failure, severe muscle weakness, and moderate sensorineural deafness and biochemically by metabolic acidosis, elevated serum pyruvate concentration, hyperalaninemia and hyperalaninuria. There have been no further descriptions in the literature since 1973.
Baraitser-Winter syndrome 1
MedGen UID:
340943
Concept ID:
C1855722
Disease or Syndrome
Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations. Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common.
Vici syndrome
MedGen UID:
340962
Concept ID:
C1855772
Disease or Syndrome
With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of EPG5-related disorder represents a continuum. At the most severe end of the spectrum is classic Vici syndrome (defined as a neurodevelopmental disorder with multisystem involvement characterized by the combination of agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive); at the milder end of the spectrum are attenuated neurodevelopmental phenotypes with variable multisystem involvement. Median survival in classic Vici syndrome appears to be 24 months, with only 10% of children surviving longer than age five years; the most common causes of death are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure. No data are available on life span in individuals at the milder end of the spectrum.
Hypoparathyroidism-retardation-dysmorphism syndrome
MedGen UID:
340984
Concept ID:
C1855840
Disease or Syndrome
HRDS is an autosomal recessive multisystem disorder characterized by intrauterine and postnatal growth retardation, infantile-onset hypoparathyroidism that can result in severe hypocalcemic seizures, dysmorphic facial features, and developmental delay (summary by Padidela et al., 2009 and Ratbi et al., 2015).
Growth retardation, small and puffy hands and feet, and eczema
MedGen UID:
343510
Concept ID:
C1856242
Disease or Syndrome
3-methylglutaconic aciduria type 5
MedGen UID:
347542
Concept ID:
C1857776
Disease or Syndrome
3-Methylglutaconic aciduria type V (MGCA5) is an autosomal recessive disorder characterized by the onset of dilated or noncompaction cardiomyopathy in infancy or early childhood. Many patients die of cardiac failure. Other features include microcytic anemia, growth retardation, mild ataxia, mild muscle weakness, genital anomalies in males, and increased urinary excretion of 3-methylglutaconic acid. Some patients may have optic atrophy or delayed psychomotor development (summary by Davey et al., 2006 and Ojala et al., 2012). For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).
Celiac disease, susceptibility to, 1
MedGen UID:
395227
Concept ID:
C1859310
Finding
Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, malabsorption, abdominal pain and distension, bloating, vomiting, and weight loss) and/or highly variable non-gastrointestinal findings (dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, iron deficiency anemia, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than non-classic celiac disease, characterized by absence of gastrointestinal symptoms.
Anophthalmia/microphthalmia-esophageal atresia syndrome
MedGen UID:
347232
Concept ID:
C1859773
Disease or Syndrome
The phenotypic spectrum of SOX2 disorder includes anophthalmia and/or microphthalmia, brain malformations, developmental delay / intellectual disability, esophageal atresia, hypogonadotropic hypogonadism (manifest as cryptorchidism and micropenis in males, gonadal dysgenesis infrequently in females, and delayed puberty in both sexes), pituitary hypoplasia, postnatal growth delay, hypotonia, seizures, and spastic or dystonic movements.
Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency
MedGen UID:
351256
Concept ID:
C1864947
Disease or Syndrome
Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by Gineau et al., 2012).
Intellectual disability, autosomal dominant 1
MedGen UID:
409857
Concept ID:
C1969562
Mental or Behavioral Dysfunction
MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).
Intellectual disability, autosomal recessive 5
MedGen UID:
370849
Concept ID:
C1970199
Mental or Behavioral Dysfunction
Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the NSUN2 gene.
Spondyloepiphyseal dysplasia, Cantu type
MedGen UID:
435975
Concept ID:
C2673649
Disease or Syndrome
An extremely rare type of spondyloepiphyseal dysplasia described in about 5 patients to date with clinical signs including short stature, peculiar facies with blepharophimosis, upward slanted eyes, abundant eyebrows and eyelashes, coarse voice, and short hands and feet.
Distal 10q deletion syndrome
MedGen UID:
436306
Concept ID:
C2674937
Disease or Syndrome
10q26 deletion syndrome is a condition that results from the loss (deletion) of a small piece of chromosome 10 in each cell. The deletion occurs on the long (q) arm of the chromosome at a position designated 10q26.\n\nThe signs and symptoms of 10q26 deletion syndrome vary widely, even among affected members of the same family. Among the more common features associated with this chromosomal change are distinctive facial features, mild to moderate intellectual disability, growth problems, and developmental delay. People with 10q26 deletion syndrome often have delayed development of speech and of motor skills such as sitting, crawling, and walking. Some have limited speech throughout life. Affected individuals may experience seizures, attention-deficit/hyperactivity disorder (ADHD), poor impulse control (impulsivity), or exhibit autistic behaviors that affect communication and social interaction.\n\nA range of facial features is seen in people with 10q26 deletion syndrome, but not all affected individuals have these features. Facial features of people with 10q26 deletion syndrome may include a prominent or beaked nose, a broad nasal bridge, a small jaw (micrognathia), malformed ears that are low set, a thin upper lip, and an unusually small head size (microcephaly). Many affected individuals have widely spaced eyes (hypertelorism) that do not look in the same direction (strabismus). Some people with this condition have a short neck with extra folds of skin (webbed neck).\n\nLess common signs and symptoms can occur in 10q26 deletion syndrome. Skeletal problems include a spine that curves to the side (scoliosis), limited movement in the elbows or other joints, or curved fifth fingers and toes (clinodactyly). Slow growth before and after birth can also occur in affected individuals. Males with this condition may have genital abnormalities, such as a small penis (micropenis), undescended testes (cryptorchidism), or the urethra opening on the underside of the penis (hypospadias). Some people with 10q26 deletion syndrome have kidney abnormalities, heart defects, breathing problems, recurrent infections, or hearing or vision problems.
Bone fragility with contractures, arterial rupture, and deafness
MedGen UID:
382811
Concept ID:
C2676285
Disease or Syndrome
Connective tissue disorder due to lysyl hydroxylase-3 deficiency is a rare, genetic disease, caused by lack of lysyl hydrohylase 3 (LH3) activity, characterized by multiple tissue and organ involvement, including skeletal abnormalities (club foot, progressive scoliosis, osteopenia, pathologic fractures), ocular involvement (flat retinae, myopia, cataracts) and hair, nail and skin anomalies (coarse, abnormally distributed hair, skin blistering, reduced palmar creases, hypoplastic nails). Patients also present intrauterine growth retardation, facial dysmorphism (flat facial profile, low-set ears, shallow orbits, short and upturned nose, downturned corners of mouth) and joint flexion contractures. Growth and developmental delay, bilateral sensorineural deafness, friable diaphragm and later-onset spontaneous vascular ruptures are additional reported features.
Syndromic X-linked intellectual disability Najm type
MedGen UID:
437070
Concept ID:
C2677903
Disease or Syndrome
CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK. X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features.
3M syndrome 1
MedGen UID:
395592
Concept ID:
C2678312
Disease or Syndrome
Three M syndrome is characterized by severe pre- and postnatal growth deficiency (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of three M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with three M syndrome have hypogonadism and occasionally hypospadias.
Glycogen storage disease IXc
MedGen UID:
442778
Concept ID:
C2751643
Disease or Syndrome
Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis.
Microcephaly, growth retardation, cataract, hearing loss, and unusual appearance
MedGen UID:
416652
Concept ID:
C2751870
Disease or Syndrome
MGAT2-congenital disorder of glycosylation
MedGen UID:
443956
Concept ID:
C2931008
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs (see, e.g., CDG1A, 212065) comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. The biochemical changes of CDGs are most readily observed in serum transferrin (TF; 190000), and the diagnosis is usually made by isoelectric focusing of this glycoprotein (reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002). Genetic Heterogeneity of Congenital Disorder of Glycosylation Type II Multiple forms of CDG type II have been identified; see CDG2B (606056) through CDG2Z (620201), and CDG2AA (620454).
COG1 congenital disorder of glycosylation
MedGen UID:
443957
Concept ID:
C2931011
Disease or Syndrome
An extremely rare form of carbohydrate deficient glycoprotein syndrome with, in the few cases reported to date, variable signs including microcephaly, growth retardation, psychomotor retardation and facial dysmorphism.
Intrauterine growth retardation with increased mitomycin c sensitivity
MedGen UID:
419040
Concept ID:
C2931307
Disease or Syndrome
Chromosome 17q23.1-q23.2 deletion syndrome
MedGen UID:
461957
Concept ID:
C3150607
Disease or Syndrome
17q23.1q23.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, microcephaly, short stature, heart defects and limb abnormalities.
Chromosome 4q21 deletion syndrome
MedGen UID:
462106
Concept ID:
C3150756
Disease or Syndrome
The 4q21 microdeletion syndrome is a newly described syndrome associated with facial dysmorphism, progressive growth restriction, severe intellectual deficit and absent or severely delayed speech.
Ogden syndrome
MedGen UID:
477078
Concept ID:
C3275447
Disease or Syndrome
Ogden syndrome (OGDNS) is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Many patients also have cardiac malformations or arrhythmias (summary by Popp et al., 2015).
Kabuki syndrome 2
MedGen UID:
477126
Concept ID:
C3275495
Disease or Syndrome
Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.
Warburg micro syndrome 3
MedGen UID:
481833
Concept ID:
C3280203
Disease or Syndrome
RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
Warburg micro syndrome 2
MedGen UID:
481844
Concept ID:
C3280214
Disease or Syndrome
RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
Feingold syndrome type 2
MedGen UID:
482119
Concept ID:
C3280489
Disease or Syndrome
Feingold syndrome is an autosomal dominant disorder characterized by variable combinations of microcephaly, limb malformations, esophageal and duodenal atresias, and learning disability/mental retardation. Hand and foot abnormalities may include hypoplastic thumbs, clinodactyly of second and fifth fingers, syndactyly (characteristically between second and third and fourth and fifth toes), and shortened or absent middle phalanges. Cardiac and renal malformations, vertebral anomalies, and deafness have also been described in a minority of patients (summary by Teszas et al., 2006). For a discussion of genetic heterogeneity of Feingold syndrome, see FGLDS1 (164280).
Chromosome 16q22 deletion syndrome
MedGen UID:
482782
Concept ID:
C3281152
Disease or Syndrome
The interstitial 16q22 deletion syndrome is a multiple congenital anomaly disorder associated with failure to thrive in infancy, poor growth, delayed psychomotor development, hypotonia, and dysmorphic features, including large anterior fontanel, high forehead, diastasis of the cranial sutures, broad nasal bridge, hypertelorism, low-set abnormal ears, and short neck. The phenotypic features and deletion sizes are variable, but deletion of 16q22 appears to be critical for manifestations of the syndrome (summary by Fujiwara et al., 1992).
Coffin-Siris syndrome 1
MedGen UID:
482831
Concept ID:
C3281201
Disease or Syndrome
Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome
MedGen UID:
762020
Concept ID:
C3541319
Disease or Syndrome
Among the Yakuts, an Asian population isolate that is located in the northeastern part of Siberia, Maksimova et al. (2010) ascertained a short stature syndrome involving autosomal recessive postnatal growth failure, small hands and feet, loss of visual acuity with abnormalities of color vision, abnormal nuclear shape in neutrophil granulocytes (Pelger-Huet anomaly; see 169400), and normal intelligence.
Cornelia de Lange syndrome 5
MedGen UID:
763817
Concept ID:
C3550903
Disease or Syndrome
Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.
Dyskeratosis congenita, autosomal recessive 5
MedGen UID:
767570
Concept ID:
C3554656
Disease or Syndrome
Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
X-linked intellectual disability, Cantagrel type
MedGen UID:
813060
Concept ID:
C3806730
Disease or Syndrome
X-linked intellectual developmental disorder-98 (XLID98) is a neurodevelopmental disorder characterized by delayed psychomotor development, poor speech, behavioral abnormalities, poor overall growth, dysmorphic facial features, and often early-onset seizures. Some carrier females are unaffected, whereas other females with mutations are affected; males tend to be more severely affected than females. It is believed that the phenotypic variability and disease manifestations in female carriers results from skewed X-inactivation or cellular mosaicism (summary by de Lange et al., 2016).
Autosomal dominant hypocalcemia 2
MedGen UID:
815573
Concept ID:
C3809243
Disease or Syndrome
An autosomal dominant hypocalcemia disease that has material basis in heterozygous mutation in the GNA11 gene on chromosome 19p13.
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1
MedGen UID:
815784
Concept ID:
C3809454
Disease or Syndrome
Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. Affected individuals show very poor, if any, normal cognitive development. Some patients are never learn to sit or walk independently (summary by Al-Sayed et al., 2013). Genetic Heterogeneity of Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies See also IHPRF2 (616801), caused by mutation in the UNC80 gene (612636) on chromosome 2q34; and IHPRF3 (616900), caused by mutation in the TBCK gene (616899) on chromosome 4q24.
Desbuquois dysplasia 2
MedGen UID:
862731
Concept ID:
C4014294
Disease or Syndrome
Desbuquois dysplasia, which belongs to the multiple dislocation group of disorders, is characterized by dislocations of large joints, severe pre- and postnatal growth retardation, joint laxity, and flat face with prominent eyes. Radiologic features include short long bones with an exaggerated trochanter that gives a 'monkey wrench' appearance to the proximal femur, and advanced carpal and tarsal ossification (summary by Bui et al., 2014). For a discussion of genetic heterogeneity of Desbuquois dysplasia, see DBQD1 (251450).
Polyendocrine-polyneuropathy syndrome
MedGen UID:
863698
Concept ID:
C4015261
Disease or Syndrome
A rare genetic disease characterized by childhood onset of multiple endocrine manifestations in combination with central and peripheral nervous system abnormalities. Reported signs and symptoms include postnatal growth retardation, moderate intellectual disability, hypogonadotropic hypogonadism, insulin-dependent diabetes mellitus, central hypothyroidism, demyelinating sensorimotor polyneuropathy, and cerebellar and pyramidal signs. Progressive hearing loss and a hypoplastic pituitary gland have also been described. Brain imaging shows moderate white matter abnormalities.
Primary coenzyme Q10 deficiency 8
MedGen UID:
908648
Concept ID:
C4225226
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Cutis laxa, autosomal dominant 3
MedGen UID:
899774
Concept ID:
C4225268
Disease or Syndrome
Autosomal dominant cutis laxa-3 is characterized by thin skin with visible veins and wrinkles, cataract or corneal clouding, clenched fingers, pre- and postnatal growth retardation, and moderate intellectual disability. In addition, patients exhibit a combination of muscular hypotonia with brisk muscle reflexes (Fischer-Zirnsak et al., 2015). For a general phenotypic description and discussion of genetic heterogeneity of autosomal dominant cutis laxa, see ARCL1 (123700).
Silver-Russell syndrome 3
MedGen UID:
894912
Concept ID:
C4225307
Disease or Syndrome
Silver-Russell syndrome-3 (SRS3) is characterized by intrauterine growth retardation with relative macrocephaly, followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face, prominent forehead, and low-set ears. Other variable features include limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay (Begemann et al., 2015; Yamoto et al., 2017). For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (180860).
Cole-Carpenter syndrome 2
MedGen UID:
905199
Concept ID:
C4225382
Disease or Syndrome
Cole-Carpenter syndrome-2 (CLCRP2) is a skeletal dysplasia associated with low bone mass or an osteogenesis imperfecta-like syndrome. It is characterized by bone fragility with craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features such as marked frontal bossing, midface hypoplasia, and micrognathia (summary by Takeyari et al., 2018).
Intellectual disability, X-linked, syndromic 33
MedGen UID:
895979
Concept ID:
C4225418
Disease or Syndrome
X-linked syndromic intellectual developmental disorder-33 (MRXS33) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and characteristic facial features (summary by O'Rawe et al., 2015).
VATER association
MedGen UID:
902479
Concept ID:
C4225671
Disease or Syndrome
VATER is a mnemonically useful acronym for the nonrandom association of vertebral defects (V), anal atresia (A), tracheoesophageal fistula with esophageal atresia (TE), and radial or renal dysplasia (R). This combination of associated defects was pointed out by Quan and Smith (1972). Nearly all cases have been sporadic. VACTERL is an acronym for an expanded definition of the association that includes cardiac malformations (C) and limb anomalies (L). The VACTERL association is a spectrum of various combinations of its 6 components, which can be a manifestation of several recognized disorders rather than a distinct anatomic or etiologic entity (Khoury et al., 1983). Also see VATER/VACTERL association with hydrocephalus (VACTERL-H; 276950) and VACTERL with or without hydrocephalus (VACTERLX; 314390).
Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy
MedGen UID:
934687
Concept ID:
C4310720
Disease or Syndrome
GRIDHH is an autosomal recessive multisystem disorder characterized by poor overall growth, impaired intellectual development, hypotonia, and variable liver dysfunction. Additional features, such as seizures and hearing loss, may also be present (summary by Kopajtich et al., 2016).
Chromosome 19q13.11 deletion syndrome, proximal
MedGen UID:
935013
Concept ID:
C4311046
Disease or Syndrome
Proximal chromosome 19q13.11 deletion syndrome is an autosomal dominant neurodevelopmental disorder characterized by delayed development, intellectual disability with poor speech, feeding difficulties, and autistic features. Some patients may have additional features, including renal tract anomalies (summary by Caubit et al., 2016).
Chromosome 19q13.11 deletion syndrome, distal
MedGen UID:
935015
Concept ID:
C4311048
Disease or Syndrome
Distal chromosome 19q13.11 deletion syndrome is an autosomal dominant neurodevelopmental disorder characterized by poor overall growth, slender habitus, microcephaly, delayed development, intellectual disability with poor or absent speech, and feeding difficulties. Additional features include dysmorphic facies, signs of ectodermal dysplasia, hand and foot anomalies, and genitourinary anomalies, particularly in males (summary by Chowdhury et al., 2014).
Al Kaissi syndrome
MedGen UID:
1611968
Concept ID:
C4540156
Disease or Syndrome
Al Kaissi syndrome (ALKAS) is an autosomal recessive developmental disorder characterized by growth retardation, spine malformation, particularly of the cervical spine, dysmorphic facial features, and delayed psychomotor development with moderate to severe intellectual disability (summary by Windpassinger et al., 2017).
Seckel syndrome 1
MedGen UID:
1637056
Concept ID:
C4551474
Disease or Syndrome
Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance (Shanske et al., 1997). Genetic Heterogeneity of Seckel Syndrome Other forms of Seckel syndrome include SCKL2 (606744), caused by mutation in the RBBP8 gene (604124) on chromosome 18q11; SCKL4 (613676), caused by mutation in the CENPJ gene (609279) on chromosome 13q12; SCKL5 (613823), caused by mutation in the CEP152 gene (613529) on chromosome 15q21; SCKL6 (614728), caused by mutation in the CEP63 gene (614724) on chromosome 3q22; SCKL7 (614851), caused by mutation in the NIN gene (608684) on chromosome 14q22; SCKL8 (615807), caused by mutation in the DNA2 gene (601810) on chromosome 10q21; SCKL9 (616777), caused by mutation in the TRAIP gene (605958) on chromosome 3p21; and SCKL10 (617253), caused by mutation in the NSMCE2 gene (617246) on chromosome 8q24. The report of a Seckel syndrome locus on chromosome 14q, designated SCKL3, by Kilinc et al. (2003) was found to be in error; see History section.
Noonan syndrome 1
MedGen UID:
1638960
Concept ID:
C4551602
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Rubinstein-Taybi syndrome due to CREBBP mutations
MedGen UID:
1639327
Concept ID:
C4551859
Disease or Syndrome
Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation.
Lissencephaly type 1 due to doublecortin gene mutation
MedGen UID:
1644310
Concept ID:
C4551968
Disease or Syndrome
DCX-related disorders include the neuronal migration disorders: Classic thick lissencephaly (more severe anteriorly), usually in males. Subcortical band heterotopia (SBH), primarily in females. Males with classic DCX-related lissencephaly typically have early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. The clinical phenotype in females with SBH varies widely with cognitive abilities that range from average or mild cognitive impairment to severe intellectual disability and language impairment. Seizures, which frequently are refractory to anti-seizure medication, may be either focal or generalized and behavioral problems may also be observed. In DCX-related lissencephaly and SBH the severity of the clinical manifestation correlates roughly with the degree of the underlying brain malformation as observed in cerebral imaging.
Cerebroretinal microangiopathy with calcifications and cysts 1
MedGen UID:
1636142
Concept ID:
C4552029
Disease or Syndrome
Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Short stature due to growth hormone secretagogue receptor deficiency
MedGen UID:
1633096
Concept ID:
C4707848
Disease or Syndrome
A rare genetic endocrine growth disease resulting from growth hormone secretagogue receptor (GHSR) deficiency. The disease has characteristics of postnatal growth delay that results in short stature. The pituitary gland is typically without morphological changes, although anterior pituitary gland hypoplasia has been reported.
Isolated growth hormone deficiency, type 5
MedGen UID:
1648500
Concept ID:
C4748435
Disease or Syndrome
Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH; 139250) and one or more of the other 5 anterior pituitary hormones. Some patients exhibit only GH deficiency, although approximately 50% of isolated GH deficiency progresses to CPHD (Gergics et al., 2021). Individuals with CPHD7 have been reported with isolated GH deficiency as well as combined deficiencies including thyroid-stimulating hormone (TSH; see 188540) and/or prolactin (PRL; 176760). In addition to severe postnatal short stature, patients exhibit delayed bone age and hypoplasia of the anterior pituitary, as well as distinctive facial dysmorphisms including frontal bossing and depressed nasal bridge (Argente et al., 2014; Verberne et al., 2020; Yamada et al., 2021). For general phenotypic information and a discussion of genetic heterogeneity of CPHD, see 613038.
Spondyloepimetaphyseal dysplasia, Isidor-Toutain type
MedGen UID:
1684771
Concept ID:
C5231478
Disease or Syndrome
The Isidor-Toutain type of spondyloepimetaphyseal dysplasia (SEMDIST) is characterized by normal birth length, early postnatal growth deficiency, severe short stature, and genu varum. Skeletal radiographs show platyspondyly and severe epiphyseal and metaphyseal changes in the lower limbs (Le Caignec et al., 2019).
Mandibuloacral dysplasia with type A lipodystrophy
MedGen UID:
1757618
Concept ID:
C5399785
Disease or Syndrome
Mandibuloacral dysplasia with type A lipodystrophy (MADA) is an autosomal recessive disorder characterized by growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, and pigmentary skin changes. The lipodystrophy is characterized by a marked acral loss of fatty tissue with normal or increased fatty tissue in the neck and trunk. Some patients may show progeroid features. Metabolic complications can arise due to insulin resistance and diabetes (Young et al., 1971; Simha and Garg, 2002; summary by Garavelli et al., 2009). See also MAD type B (MADB; 608612), which is caused by mutation in the ZMPSTE24 gene (606480).
Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant
MedGen UID:
1723138
Concept ID:
C5436546
Disease or Syndrome
Autosomal dominant growth hormone insensitivity syndrome with immune dysregulation-2 (GHISID2) is a congenital disorder characterized by short stature due to insensitivity to growth hormone (GH1; 139250). Affected individuals usually have delayed bone age, delayed puberty, and decreased serum IGF1 (147440). Some patients may have features of mild immune dysregulation, such as eczema, increased serum IgE, asthma, or celiac disease (summary by Klammt et al., 2018).
Mandibuloacral dysplasia progeroid syndrome
MedGen UID:
1741713
Concept ID:
C5436867
Disease or Syndrome
Mandibuloacral dysplasia progeroid syndrome (MDPS) is an autosomal recessive severe laminopathy-like disorder characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis, and hypertension (Elouej et al., 2020).
Ritscher-Schinzel syndrome 3
MedGen UID:
1744611
Concept ID:
C5436883
Disease or Syndrome
Ritscher-Schinzel syndrome-3 (RTSC3) is characterized by craniocerebellocardiac anomalies and severe postnatal growth restriction, as well as complicated skeletal malformations, including vertebral body hypoossification, sternal aplasia, and chondrodysplasia punctata. Other features include developmental delay, ocular anomalies, periventricular nodular heterotopia, and proteinuria (Kato et al., 2020). For a discussion of genetic heterogeneity of Ritscher-Schinzel syndrome, see RTSC1 (220210).
Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2
MedGen UID:
1782253
Concept ID:
C5543057
Disease or Syndrome
Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies-2 (SSFSC2) is characterized by thin and short long bones, distinctive facial dysmorphism, and dental and skeletal abnormalities, in the absence of developmental delay or intellectual disability. Cardiac anomalies have been reported in some patients (Lin et al., 2021). For a discussion of genetic heterogeneity of SSFSC, see SSFSC1 (617877).
Short stature, Dauber-Argente type
MedGen UID:
1794178
Concept ID:
C5561968
Disease or Syndrome
Short stature of the Dauber-Argente type (SSDA) is characterized by progressive postnatal growth failure, moderate microcephaly, thin long bones, and mildly decreased bone density. Patients have elevated circulating levels of total IGF1 (147440) due to impaired proteolysis of IGFBP3 (146732) and IGFBP5 (146734), resulting in reduced free IGF1 (Dauber et al., 2016).
Chopra-Amiel-Gordon syndrome
MedGen UID:
1794185
Concept ID:
C5561975
Disease or Syndrome
Chopra-Amiel-Gordon syndrome (CAGS) is an autosomal dominant disorder characterized by developmental delay and/or impaired intellectual development, speech delay, facial dysmorphism, and variable other features, including recurrent bacterial infections, ophthalmologic abnormalities, and nonspecific brain abnormalities (Chopra et al., 2021).
Rauch-Steindl syndrome
MedGen UID:
1794271
Concept ID:
C5562061
Disease or Syndrome
Rauch-Steindl syndrome (RAUST) is characterized by poor pre- and postnatal growth, sometimes with short stature and small head circumference, characteristic dysmorphic facial features, and variable developmental delay with delayed motor and speech acquisition and impaired intellectual function that can be mild. Other features may include hypotonia and behavioral abnormalities. The phenotype represents a mild form of Wolf-Hirschhorn syndrome (WHS; 194190), which is a contiguous gene deletion syndrome caused by heterozygous deletion of several genes on chromosome 4p16. The clinical features of RAUST are similar to but milder than those of WHS, with less severe dysmorphic facial features, less severe developmental disabilities in general, and absence of a seizure disorder. The phenotype and expressivity of RAUST is highly variable (summary by Rauch et al., 2001; Zanoni et al., 2021).
Combined immunodeficiency due to GINS1 deficiency
MedGen UID:
1799555
Concept ID:
C5568132
Disease or Syndrome
Immunodeficiency-55 is an autosomal recessive primary immunodeficiency characterized by intrauterine growth retardation, natural killer (NK) cell deficiency, and chronic neutropenia. Most patients also have postnatal growth retardation. Other clinical manifestations include mild facial dysmorphism, dry or eczematous skin, and recurrent infections with both viruses and bacteria. The disorder appears to result from a defect in DNA replication causing blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells (summary by Cottineau et al., 2017).
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1
MedGen UID:
1808104
Concept ID:
C5677021
Disease or Syndrome
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1) is characterized by cranial involvement with macrocrania at birth, brachycephaly, anomalies of middle fossa structures including hypoplasia of corpus callosum, enlargement of septum pellucidum, and dilated lateral ventricles, as well as cortical atrophy and hypodensity of the gray matter. Facial dysmorphisms include flat face, hypertelorism, epicanthal folds, synophrys, broad nasal bridge, cleft lip and cleft palate, and low-set posteriorly rotated ears. Patients also exhibit short neck and multiple costal and vertebral anomalies. The face is rather characteristic, and various authors have consistently reported affable/friendly personality, despite intellectual delay (summary by Alanay et al., 2014). Genetic Heterogeneity of Craniofacial Dysmorphism, Skeletal Anomalies, and Mental Retardation Syndrome CFSMR2 (616994) is caused by mutation in the RAB5IF gene (619960) on chromosome 20q11.

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Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I
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Milani D, Manzoni FM, Pezzani L, Ajmone P, Gervasini C, Menni F, Esposito S
Ital J Pediatr 2015 Jan 20;41:4. doi: 10.1186/s13052-015-0110-1. PMID: 25599811Free PMC Article
Walenkamp MJ, Losekoot M, Wit JM
Endocr Dev 2013;24:128-37. Epub 2013 Feb 1 doi: 10.1159/000342841. PMID: 23392101

Recent clinical studies

Etiology

Cerasani J, Ceroni F, De Cosmi V, Mazzocchi A, Morniroli D, Roggero P, Mosca F, Agostoni C, Giannì ML
Nutrients 2020 Apr 21;12(4) doi: 10.3390/nu12041155. PMID: 32326178Free PMC Article
Denny L, Coles S, Blitz R
Am Fam Physician 2017 Oct 15;96(8):515-522. PMID: 29094891
Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I
Nat Rev Endocrinol 2017 Feb;13(2):105-124. Epub 2016 Sep 2 doi: 10.1038/nrendo.2016.138. PMID: 27585961
de Munnik SA, Hoefsloot EH, Roukema J, Schoots J, Knoers NV, Brunner HG, Jackson AP, Bongers EM
Orphanet J Rare Dis 2015 Sep 17;10:114. doi: 10.1186/s13023-015-0322-x. PMID: 26381604Free PMC Article
Eggermann T
Am J Med Genet C Semin Med Genet 2010 Aug 15;154C(3):355-64. doi: 10.1002/ajmg.c.30274. PMID: 20803658

Diagnosis

Denny L, Coles S, Blitz R
Am Fam Physician 2017 Oct 15;96(8):515-522. PMID: 29094891
Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I
Nat Rev Endocrinol 2017 Feb;13(2):105-124. Epub 2016 Sep 2 doi: 10.1038/nrendo.2016.138. PMID: 27585961
de Munnik SA, Hoefsloot EH, Roukema J, Schoots J, Knoers NV, Brunner HG, Jackson AP, Bongers EM
Orphanet J Rare Dis 2015 Sep 17;10:114. doi: 10.1186/s13023-015-0322-x. PMID: 26381604Free PMC Article
Milani D, Manzoni FM, Pezzani L, Ajmone P, Gervasini C, Menni F, Esposito S
Ital J Pediatr 2015 Jan 20;41:4. doi: 10.1186/s13052-015-0110-1. PMID: 25599811Free PMC Article
Boyle MI, Jespersgaard C, Brøndum-Nielsen K, Bisgaard AM, Tümer Z
Clin Genet 2015 Jul;88(1):1-12. Epub 2014 Oct 28 doi: 10.1111/cge.12499. PMID: 25209348

Therapy

Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I
Nat Rev Endocrinol 2017 Feb;13(2):105-124. Epub 2016 Sep 2 doi: 10.1038/nrendo.2016.138. PMID: 27585961
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Abel EL
Drug Alcohol Depend 1984 Sep;14(1):1-10. doi: 10.1016/0376-8716(84)90012-7. PMID: 6386408

Prognosis

Rockstroh D, Pfäffle H, Le Duc D, Rößler F, Schlensog-Schuster F, Heiker JT, Kratzsch J, Kiess W, Lemke JR, Abou Jamra R, Pfäffle R
Eur J Endocrinol 2019 Jan 1;180(1):K1-K13. doi: 10.1530/EJE-18-0601. PMID: 30400067
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J Matern Fetal Neonatal Med 2018 Apr;31(8):1105-1107. Epub 2017 Apr 3 doi: 10.1080/14767058.2017.1306512. PMID: 28293959
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Clinical prediction guides

Musante L, Faletra F, Meier K, Tomoum H, Najarzadeh Torbati P, Blair E, North S, Gärtner J, Diegmann S, Beiraghi Toosi M, Ashrafzadeh F, Ghayoor Karimiani E, Murphy D, Murru FM, Zanus C, Magnolato A, La Bianca M, Feresin A, Girotto G, Gasparini P, Costa P, Carrozzi M
Am J Med Genet A 2022 Sep;188(9):2652-2665. Epub 2022 Jun 7 doi: 10.1002/ajmg.a.62852. PMID: 35670379Free PMC Article
Netchine I, Azzi S, Le Bouc Y, Savage MO
Best Pract Res Clin Endocrinol Metab 2011 Feb;25(1):181-90. doi: 10.1016/j.beem.2010.08.005. PMID: 21396584
Eggermann T
Am J Med Genet C Semin Med Genet 2010 Aug 15;154C(3):355-64. doi: 10.1002/ajmg.c.30274. PMID: 20803658
Eggermann T, Gonzalez D, Spengler S, Arslan-Kirchner M, Binder G, Schönherr N
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Abel EL
Drug Alcohol Depend 1984 Sep;14(1):1-10. doi: 10.1016/0376-8716(84)90012-7. PMID: 6386408

Recent systematic reviews

Wannes S, El Ahmer I, Rjiba K, Jemmali N, Abdallah HH, Haj RB, Achour A, Bouzidi H, Saad A, Mougou S, Mahjoub B
Growth Horm IGF Res 2023 Aug;71:101550. Epub 2023 Jul 25 doi: 10.1016/j.ghir.2023.101550. PMID: 37531800
Schigt H, Bald M, van der Eerden BCJ, Gal L, Ilenwabor BP, Konrad M, Levine MA, Li D, Mache CJ, Mackin S, Perry C, Rios FJ, Schlingmann KP, Storey B, Trapp CM, Verkerk AJMH, Zillikens MC, Touyz RM, Hoorn EJ, Hoenderop JGJ, de Baaij JHF
J Clin Endocrinol Metab 2023 Aug 18;108(9):e754-e768. doi: 10.1210/clinem/dgad147. PMID: 36916904Free PMC Article

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