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Premature birth

MedGen UID:
57721
Concept ID:
C0151526
Pathologic Function
Synonyms: Birth, Premature; Birth, Preterm; Births, Premature; Births, Preterm; Premature Birth; Premature Births; Preterm Birth; Preterm Births
SNOMED CT: Premature delivery (282020008)
 
HPO: HP:0001622

Definition

The birth of a baby of less than 37 weeks of gestational age. [from HPO]

Conditions with this feature

Smith-Lemli-Opitz syndrome
MedGen UID:
61231
Concept ID:
C0175694
Disease or Syndrome
Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple-anomaly / cognitive impairment syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase. It is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide; individuals with normal development and only minor malformations have been described.
Nager syndrome
MedGen UID:
120519
Concept ID:
C0265245
Disease or Syndrome
Nager syndrome is the prototype for a group of disorders collectively referred to as the acrofacial dysostoses (AFDs), which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of Nager syndrome include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. The presence of anterior upper-limb defects and the typical lack of lower-limb involvement distinguishes Nager syndrome from Miller syndrome (263750), another rare AFD; however, distinguishing Nager syndrome from other AFDs, including Miller syndrome, can be challenging (summary by Bernier et al., 2012).
Atelosteogenesis type I
MedGen UID:
82701
Concept ID:
C0265283
Congenital Abnormality
The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.
Congenital secretory diarrhea, chloride type
MedGen UID:
78631
Concept ID:
C0267662
Disease or Syndrome
Congenital secretory chloride diarrhea is an autosomal recessive form of severe chronic diarrhea characterized by excretion of large amounts of watery stool containing high levels of chloride, resulting in dehydration, hypokalemia, and metabolic alkalosis. The electrolyte disorder resembles the renal disorder Bartter syndrome (see 607364), except that chloride diarrhea is not associated with calcium level abnormalities (summary by Choi et al., 2009). Genetic Heterogeneity of Diarrhea Other forms of diarrhea include DIAR2 (251850), caused by mutation in the MYO5B gene (606540) on 18q21; DIAR3 (270420), caused by mutation in the SPINT2 gene (605124) on 19q13; DIAR4 (610370), caused by mutation in the NEUROG3 gene (604882) on 10q21; DIAR5 (613217), caused by mutation in the EPCAM gene (185535) on 2p21; DIAR6 (614616), caused by mutation in the GUCY2C gene (601330) on 12p12; DIAR7 (615863) caused by mutation in the DGAT1 gene (604900) on 8q24; DIAR8 (616868), caused by mutation in the SLC9A3 gene (182307) on 5p15; DIAR9 (618168), caused by mutation in the WNT2B gene (601968) on 1p13; DIAR10 (618183), caused by mutation in the PLVAP gene (607647) on 19p13; DIAR11 (618662), caused by deletion of the intestine critical region (ICR) on chromosome 16p13, resulting in loss of expression of the flanking gene PERCC1 (618656); DIAR12 (619445), caused by mutation in the STX3 gene (600876) on 11q12; and DIAR13 (620357), caused by mutation in the ACSL5 gene (605677) on chromosome 10q25.
GM1 gangliosidosis type 2
MedGen UID:
120625
Concept ID:
C0268272
Disease or Syndrome
GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.
Osteogenesis imperfecta, recessive perinatal lethal
MedGen UID:
75673
Concept ID:
C0268358
Congenital Abnormality
COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent, wear down, and break easily. COL1A1/2-OI has been classified into four types based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four more common OI types are now referred to as follows: Classic non-deforming OI with blue sclerae (previously OI type I). Perinatally lethal OI (previously OI type II). Progressively deforming OI (previously OI type III). Common variable OI with normal sclerae (previously OI type IV).
Severe X-linked myotubular myopathy
MedGen UID:
98374
Concept ID:
C0410203
Congenital Abnormality
X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM), is characterized by muscle weakness that ranges from severe to mild. Approximately 80% of affected males present with severe (classic) X-MTM characterized by polyhydramnios, decreased fetal movement, and neonatal weakness, hypotonia, and respiratory failure. Motor milestones are significantly delayed and most individuals fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most individuals requiring 24-hour ventilatory assistance. It is estimated that at least 25% of boys with severe X-MTM die in the first year of life, and those who survive rarely live into adulthood. Males with mild or moderate X-MTM (~20%) achieve motor milestones more quickly than males with the severe form; many ambulate independently, and may live into adulthood. Most require gastrostomy tubes and/or ventilator support. In all subtypes of X-MTM, the muscle disease is not obviously progressive. Female carriers of X-MTM are generally asymptomatic, although manifesting heterozygotes are increasingly being identified. In affected females, symptoms range from severe, generalized weakness presenting in childhood, with infantile onset similar to affected male patients, to mild (often asymmetric) weakness manifesting in adulthood. Affected adult females may experience progressive respiratory decline and ultimately require ventilatory support.
Costello syndrome
MedGen UID:
108454
Concept ID:
C0587248
Disease or Syndrome
While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.
Autosomal recessive congenital ichthyosis 4B
MedGen UID:
108615
Concept ID:
C0598226
Disease or Syndrome
Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management. Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection. Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma. Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.
X-linked intellectual disability-short stature-overweight syndrome
MedGen UID:
901885
Concept ID:
C0796218
Disease or Syndrome
X-linked intellectual developmental disorder-12 (XLID12) is characterized by borderline to severe intellectual disability with variable neurologic features, short stature, and elevated body mass index (BMI) (Kumar et al., 2015).
Sialic acid storage disease, severe infantile type
MedGen UID:
203367
Concept ID:
C1096902
Disease or Syndrome
Free sialic acid storage disorders (FSASDs) are a spectrum of neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. Historically, FSASD was divided into separate allelic disorders: Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD). The mildest type was Salla disease, characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures. Salla disease was named for a municipality in Finnish Lapland where a specific founder variant is relatively prevalent. However, the term Salla has been used in the literature to refer to less severe FSASD. More severe FSASD is historically referred to as ISSD, and is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.
Cardio-facio-cutaneous syndrome
MedGen UID:
266149
Concept ID:
C1275081
Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Fetal akinesia deformation sequence 1
MedGen UID:
220903
Concept ID:
C1276035
Disease or Syndrome
Decreased fetal activity associated with multiple joint contractures, facial anomalies and pulmonary hypoplasia. Ultrasound examination may reveal polyhydramnios, ankylosis, scalp edema, and decreased chest movements (reflecting pulmonary hypoplasia).
Familial hyperthyroidism due to mutations in TSH receptor
MedGen UID:
373154
Concept ID:
C1836706
Disease or Syndrome
A rare hyperthyroidism characterized by mild to severe hyperthyroidism, presence of goiter, absence of features of autoimmunity, frequent relapses while on treatment and a positive family history.
Emanuel syndrome
MedGen UID:
323030
Concept ID:
C1836929
Disease or Syndrome
Emanuel syndrome is characterized by pre- and postnatal growth deficiency, microcephaly, hypotonia, severe developmental delays, ear anomalies, preauricular tags or pits, cleft or high-arched palate, congenital heart defects, kidney abnormalities, and genital abnormalities in males.
Ichthyosis prematurity syndrome
MedGen UID:
324839
Concept ID:
C1837610
Disease or Syndrome
Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management. Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection. Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma. Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.
Gaucher disease perinatal lethal
MedGen UID:
374996
Concept ID:
C1842704
Disease or Syndrome
Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.
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).
Hypomyelinating leukodystrophy 3
MedGen UID:
342403
Concept ID:
C1850053
Disease or Syndrome
Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (summary by Feinstein et al., 2010). The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; 312080), which is caused by mutation in the PLP1 gene (300401). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
Bartter disease type 2
MedGen UID:
343428
Concept ID:
C1855849
Disease or Syndrome
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Fowler syndrome
MedGen UID:
384026
Concept ID:
C1856972
Disease or Syndrome
The proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome is a rare, autosomal recessive, usually prenatally lethal disorder characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. It is usually diagnosed by ultrasound between 26 and 33 weeks' gestation (summary by Meyer et al., 2010). Rarely, affected individuals may survive, but are severely impaired with almost no neurologic development (Kvarnung et al., 2016).
Ventriculomegaly-cystic kidney disease
MedGen UID:
346584
Concept ID:
C1857423
Disease or Syndrome
Ventriculomegaly with cystic kidney disease is a severe autosomal recessive developmental disorder characterized by onset in utero of dilated cerebral ventricles and microscopic renal tubular cysts. The pregnancies of affected individuals are associated with increased alpha-fetoprotein (AFP). Most affected pregnancies have been terminated (summary by Slavotinek et al., 2015). See also 602200 for a disorder characterized by ventriculomegaly and defects of the radius and kidney.
Yunis-Varon syndrome
MedGen UID:
341818
Concept ID:
C1857663
Disease or Syndrome
Yunis-Varon syndrome (YVS) is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy (summary by Campeau et al., 2013).
Autosomal recessive distal spinal muscular atrophy 1
MedGen UID:
388083
Concept ID:
C1858517
Disease or Syndrome
Autosomal recessive distal hereditary motor neuronopathy-1 (HMNR1) is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, most infants with the severe form of the disease die before 2 years of age. Affected individuals present in infancy with inspiratory stridor, weak cry, recurrent bronchopneumonia, and swallowing difficulties. The disorder is caused by distal and progressive motor neuronopathy resulting in muscle weakness (summary by Perego et al., 2020). Genetic Heterogeneity of Autosomal Recessive Distal Hereditary Motor Neuronopathy See also HMNR2 (605726), caused by mutation in the SIGMAR1 gene (601978); HMNR3 (607088) (encompassing Harding HMN types III and IV), which maps to chromosome 11q13; HMNR4 (611067), caused by mutation in the PLEKHG5 gene (611101); HMNR5 (614881), caused by mutation in the DNAJB2 gene (604139); HMNR6 (620011), caused by mutation in the REEP1 gene (609139); HMNR7 (619216), caused by mutation in the VWA1 gene (611901); HMNR8 (618912), caused by mutation in the SORD gene (182500); HMNR9 (620402), caused by mutation in the COQ7 gene (601683); and HMRN10 (620542), caused by mutation in the VRK1 gene (602168).
Microcephaly 2, primary, autosomal recessive, with or without cortical malformations
MedGen UID:
346929
Concept ID:
C1858535
Disease or Syndrome
In WDR62 primary microcephaly (WDR62-MCPH), microcephaly (occipitofrontal circumference [OFC] = -2 SD) is usually present at birth, but in some instances becomes evident later in the first year of life. Growth is otherwise normal. Except for brain malformations in most affected individuals, no other congenital malformations are observed. Central nervous system involvement can include delayed motor development, mild-to-severe intellectual disability (ID), behavior problems, epilepsy, spasticity, and ataxia.
Chondrodysplasia Blomstrand type
MedGen UID:
395189
Concept ID:
C1859148
Disease or Syndrome
Blomstrand chondrodysplasia is an autosomal recessive disorder characterized by short limbs, polyhydramnios, hydrops fetalis, facial anomalies, increased bone density, and advanced skeletal maturation (summary by Loshkajian et al., 1997).
Pyridoxal phosphate-responsive seizures
MedGen UID:
350498
Concept ID:
C1864723
Disease or Syndrome
Untreated pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency, characterized by a range of seizure types, is "classic" (i.e., seizure onset in the neonatal period) in about 90% of affected individuals and "late onset" (seizure onset after the neonatal period) in about 10%. In classic PNPO deficiency, seizures (including status epilepticus) often begin on the first day of life and typically before age two weeks. In both classic and late-onset untreated PNPO deficiency, seizure semiology varies from myoclonic to clonic or tonic seizures, and seizures are typically resistant to common anti-seizure medications. Independent of age of onset, seizures respond to life-long treatment with a B6 vitamer: pyridoxal 5'-phosphate (PLP) in about 60% of affected individuals and pyridoxine (PN) in about 40%. About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some individuals have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures.
Bartter disease type 4A
MedGen UID:
355430
Concept ID:
C1865270
Disease or Syndrome
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal (or neonatal) forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Bartter disease type 1
MedGen UID:
355727
Concept ID:
C1866495
Disease or Syndrome
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Respiratory distress syndrome in premature infants
MedGen UID:
368840
Concept ID:
C1968593
Disease or Syndrome
The main cause of respiratory distress syndrome (RDS) in premature infants is a developmental deficiency of pulmonary surfactant. The frequency of RDS is inversely proportional to gestational age. However, not all infants born prematurely develop RDS, suggesting that there may be susceptibility factors. Because multiple factors can contribute to the pathogenesis of RDS specifically in premature infants, the etiology is considered to be multifactorial (summaries by Ramet et al., 2000; Clark and Clark, 2005). Pathogenic germline mutations in several genes involved in surfactant metabolism, including SFTPB (178640) and SFTPC (178620), can cause clinical features of respiratory distress syndrome in term neonates, children, and adults, disorders referred to as 'surfactant metabolism dysfunction' (see, e.g., SMDP1, 265120). Susceptibility to the development of RDS in premature infants may be associated with polymorphisms in surfactant genes, such as surfactant protein A1 (SFTPA1; 178630), SFTPB, and SFTPC (see MOLECULAR GENETICS).
Polyhydramnios, megalencephaly, and symptomatic epilepsy
MedGen UID:
370203
Concept ID:
C1970203
Disease or Syndrome
A rare genetic neurological disorder with characteristics of pregnancy complicated by polyhydramnios, severe intractable epilepsy presenting in infancy, severe hypotonia, decreased muscle mass, global developmental delay, craniofacial dysmorphism (long face, large forehead, peaked eyebrows, broad nasal bridge, hypertelorism, large mouth with thick lips), and macrocephaly due to megalencephaly and hydrocephalus in most patients. Additional features that have been reported include cardiac anomalies like atrial septal defects, diabetes insipidus and nephrocalcinosis among others.
Compton-North congenital myopathy
MedGen UID:
393406
Concept ID:
C2675527
Disease or Syndrome
Congenital myopathy-12 (CMYP12) is an autosomal recessive disorder characterized by severe neonatal hypotonia resulting in feeding difficulties and respiratory failure within the first months of life. There is evidence of the disorder in utero, with decreased fetal movements and polyhydramnios. Additional features may include high-arched palate and contractures. Skeletal muscle biopsy shows myopathic changes with disrupted sarcomeres and minicore-like structures (Compton et al., 2008). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Diamond-Blackfan anemia 1
MedGen UID:
390966
Concept ID:
C2676137
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia or no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.
Ehlers-Danlos syndrome, dermatosparaxis type
MedGen UID:
397792
Concept ID:
C2700425
Disease or Syndrome
Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (Lapiere et al., 1971). Lapiere and Nusgens (1993) reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human.
Hyperuricemia, pulmonary hypertension, renal failure, alkalosis syndrome
MedGen UID:
462559
Concept ID:
C3151209
Disease or Syndrome
HUPRA syndrome is a severe autosomal recessive multisystem disorder characterized by onset in infancy of progressive renal failure leading to electrolyte imbalances, metabolic alkalosis, pulmonary hypertension, hypotonia, and delayed development. Affected individuals are born prematurely (summary by Belostotsky et al., 2011).
Mitochondrial complex V (ATP synthase) deficiency nuclear type 2
MedGen UID:
481329
Concept ID:
C3279699
Disease or Syndrome
Mitochondrial encephalo-cardio-myopathy due to <i>TMEM70</i> mutation is characterized by early neonatal onset of hypotonia, hypetrophic cardiomyopathy and apneic spells within hours after birth accompanied by lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria.
Trichohepatoenteric syndrome 2
MedGen UID:
482919
Concept ID:
C3281289
Disease or Syndrome
Trichohepatoenteric syndrome (THES), generally considered to be a neonatal enteropathy, is characterized by intractable diarrhea (seen in almost all affected children), woolly hair (seen in all), intrauterine growth restriction, facial dysmorphism, and short stature. Additional findings include poorly characterized immunodeficiency, recurrent infections, skin abnormalities, and liver disease. Mild intellectual disability (ID) is seen in about 50% of affected individuals. Less common findings include congenital heart defects and platelet anomalies. To date 52 affected individuals have been reported.
Cholestasis, intrahepatic, of pregnancy, 1
MedGen UID:
762759
Concept ID:
C3549845
Disease or Syndrome
Intrahepatic cholestasis of pregnancy is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Some women with ICP may also be susceptible to oral contraceptive-induced cholestasis (OCIC) (summary by Pasmant et al., 2012). Genetic Heterogeneity of Intrahepatic Cholestasis of Pregnancy See also ICP3 (614972), caused by mutation in the ABCB4 gene (171060).
Cholestasis, intrahepatic, of pregnancy, 3
MedGen UID:
767155
Concept ID:
C3554241
Disease or Syndrome
Intrahepatic cholestasis of pregnancy is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Women with ICP are also susceptible to oral contraceptive-induced cholestasis (OCIC). Ursodeoxycholic acid (UDCA) is an effective treatment for conditions caused by ABCB4 mutations (summary by Pasmant et al., 2012). Mutation in the ABCB4 gene accounts for about 15% of ICP cases (summary by Ziol et al., 2008). For a discussion of genetic heterogeneity of ICP, see ICP1 (147480).
Dysmorphism-conductive hearing loss-heart defect syndrome
MedGen UID:
767688
Concept ID:
C3554774
Disease or Syndrome
A rare multiple congenital anomalies syndrome with characteristics of distinctive facial appearance (low frontal hairline, bilateral ptosis, prominent eyes, flat midface, broad, ?at nares, Cupid''s bow upper lip vermilion and small, low-set, posteriorly rotated ears), cleft palate, conductive hearing loss, heart defects (atrial or ventricular septal defect) and mild developmental delay/intellectual disability.
Nemaline myopathy 10
MedGen UID:
863797
Concept ID:
C4015360
Disease or Syndrome
Nemaline myopathy-10 (NEM10) is an autosomal recessive severe congenital myopathy characterized by early-onset generalized muscle weakness and hypotonia with respiratory insufficiency and feeding difficulties. Many patients present antenatally with decreased fetal movements, and most die of respiratory failure in early infancy (summary by Yuen et al., 2014). Patients with a stable and much milder disease course have been described (Schatz et al., 2018). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM3 (161800).
Motor developmental delay due to 14q32.2 paternally expressed gene defect
MedGen UID:
863995
Concept ID:
C4015558
Disease or Syndrome
Temple syndrome is a short stature disorder of imprinting. The cardinal features are low birth weight, hypotonia and motor delay, feeding problems early in life, early puberty, and significantly reduced final height. Facial features include a broad forehead and short nose with a wide nasal tip, and the majority of patients have small hands and feet. However, many of the clinical features are nonspecific, making diagnosis difficult. In addition, isodisomy may uncover recessive disorders, which may influence the phenotype in maternal uniparental disomy of chromosome 14 (UPD14mat) cases (summary by Ioannides et al., 2014).
Spinal muscular atrophy with congenital bone fractures 2
MedGen UID:
907910
Concept ID:
C4225176
Disease or Syndrome
Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by Knierim et al., 2016). For a discussion of genetic heterogeneity of spinal muscular atrophy with congenital bone fractures, see SMABF1 (616866).
Spinal muscular atrophy with congenital bone fractures 1
MedGen UID:
896011
Concept ID:
C4225177
Disease or Syndrome
Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by Knierim et al., 2016). Genetic Heterogeneity of Spinal Muscular Atrophy With Congenital Bone Fractures See also SMABF2 (616867), caused by mutation in the ASCC1 gene (614215) on chromosome 10q22.
Progeroid and marfanoid aspect-lipodystrophy syndrome
MedGen UID:
934763
Concept ID:
C4310796
Disease or Syndrome
The marfanoid-progeroid-lipodystrophy syndrome (MFLS) is characterized by congenital lipodystrophy, premature birth with an accelerated linear growth disproportionate to weight gain, and progeroid appearance with distinct facial features, including proptosis, downslanting palpebral fissures, and retrognathia. Other characteristic features include arachnodactyly, digital hyperextensibility, myopia, dural ectasia, and normal psychomotor development (Takenouchi et al., 2013). Takenouchi et al. (2013) noted phenotypic overlap with Marfan syndrome (154700) and Shprintzen-Goldberg craniosynostosis syndrome (182212).
Bartter disease type 4B
MedGen UID:
934772
Concept ID:
C4310805
Disease or Syndrome
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Bartter disease type 5
MedGen UID:
934787
Concept ID:
C4310820
Disease or Syndrome
Antenatal Bartter syndrome is a potentially life-threatening disease characterized by fetal polyuria, polyhydramnios, prematurity, and postnatal polyuria with persistent renal salt wasting. In transient antenatal Bartter syndrome-5, the onset of polyhydramnios and labor occur several weeks earlier than in other forms of Bartter syndrome. Polyuria lasts from a few days to 6 weeks, ending around 30 to 33 weeks of gestational age. Other features in the neonatal period include hypercalciuria, causing nephrocalcinosis in some cases, as well as hyponatremia, hypokalemia, and elevated renin and aldosterone; these subsequently resolve or normalize, although nephrocalcinosis may persist (Laghmani et al., 2016).
Intellectual disability, X-linked, syndromic, 35
MedGen UID:
1392054
Concept ID:
C4478383
Disease or Syndrome
Diencephalic-mesencephalic junction dysplasia syndrome 1
MedGen UID:
1615973
Concept ID:
C4538630
Disease or Syndrome
Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present (summary by Aran et al., 2016 and Guemez-Gamboa et al., 2018). Genetic Heterogeneity of Diencephalic-Mesencephalic Junction Dysplasia Syndrome See also DMJDS2 (618646), caused by mutation in the GSX2 gene (616253) on chromosome 4q12.
Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy
MedGen UID:
1615361
Concept ID:
C4540493
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA) is an autosomal recessive disorder characterized by severe global developmental delay with poor motor and intellectual function apparent soon after birth, as well as postnatal progressive microcephaly. Most patients develop early-onset, frequent, and often intractable seizures, compatible with an epileptic encephalopathy. Other features include poor feeding, poor overall growth, absent speech, poor or absent eye contact, inability to achieve walking, hypotonia, and peripheral spasticity. Brain imaging usually shows progressive cerebral atrophy, thin corpus callosum, and abnormalities in myelination. Death in childhood may occur (summary by Siekierska et al., 2019).
Geleophysic dysplasia 3
MedGen UID:
1615724
Concept ID:
C4540511
Congenital Abnormality
Geleophysic dysplasia, a progressive condition resembling a lysosomal storage disorder, is characterized by short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features, progressive cardiac valvular disease, and thickened skin. Intellect is normal. Major findings are likely to be present in the first year of life. Cardiac, respiratory, and lung involvement result in death before age five years in approximately 33% of individuals with ADAMTSL2-related geleophysic dysplasia.
Mitochondrial complex 1 deficiency, nuclear type 30
MedGen UID:
1648313
Concept ID:
C4746985
Disease or Syndrome
Cardiac, facial, and digital anomalies with developmental delay
MedGen UID:
1648330
Concept ID:
C4748484
Disease or Syndrome
CAFDADD is a multisystemic developmental disorder with variable cardiac and digital anomalies and facial dysmorphism. Some patients may have seizures and ocular/aural abnormalities (Tokita et al., 2018).
Mitochondrial complex 1 deficiency, nuclear type 25
MedGen UID:
1648366
Concept ID:
C4748806
Disease or Syndrome
Trichohepatoneurodevelopmental syndrome
MedGen UID:
1648322
Concept ID:
C4748898
Disease or Syndrome
Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018).
Congenital disorder of glycosylation with defective fucosylation 2
MedGen UID:
1676187
Concept ID:
C5193028
Disease or Syndrome
Neurodevelopmental disorder with seizures and speech and walking impairment
MedGen UID:
1672912
Concept ID:
C5193119
Disease or Syndrome
Neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI) is an autosomal recessive disorder with onset in infancy. Patients show global developmental delay, particularly of speech acquisition, as well as walking difficulties due to hypotonia, hypertonia, spasticity, or poor coordination. Other features include seizures, mild dysmorphic features, and variable short stature. The pregnancies tend to be complicated by hyper- or hypotension (summary by Ganapathi et al., 2019).
Hypopigmentation, organomegaly, and delayed myelination and development
MedGen UID:
1684826
Concept ID:
C5203300
Disease or Syndrome
Hypopigmentation, organomegaly, and delayed myelination and development (HOD) is characterized by hypopigmented skin and hair with normally pigmented irides; organomegaly including enlargement of liver, kidney, and spleen; and delayed myelination on brain MRI accompanied by developmental delay in both gross and fine motor skills. Biopsy findings from skin and other organs are consistent with a lysosomal storage disorder (Nicoli et al., 2019).
Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
MedGen UID:
1684840
Concept ID:
C5231431
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA) is an autosomal recessive disorder characterized by severe global developmental delay, usually with hypotonia and absence of spontaneous movements other than head control, impaired intellectual development with absent speech, distal contractures, progressive microcephaly, dysmorphic features, and distal skeletal abnormalities, such as rocker-bottom feet and clenched hands with camptodactyly. Brain imaging tends to show a simplified gyral pattern of the cerebral cortex, delayed myelination, thin corpus callosum, and hypoplasia of the brainstem and cerebellum. The disorder may be complicated by feeding and/or breathing difficulties, often resulting in death in infancy (summary by Magini et al., 2019).
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
MedGen UID:
1716098
Concept ID:
C5394091
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation (NEDHRIT) is a severe autosomal recessive disorder characterized by neonatal respiratory distress, poor feeding, and impaired global development. Affected individuals are unable to walk or speak and have poor or absent eye contact. Some patients may develop seizures (summary by Wagner et al., 2020).
Combined oxidative phosphorylation deficiency 40
MedGen UID:
1714731
Concept ID:
C5394232
Disease or Syndrome
Combined oxidative phosphorylation deficiency-40 (COXPD40) is an autosomal recessive mitochondrial disorder with onset in utero or soon after birth. Affected individuals have severe hypertrophic cardiomyopathy, poor growth, and sensorineural hearing loss. Laboratory studies show evidence of mitochondrial dysfunction, such as lactic acidosis. Patient-derived tissues and cells show variably decreased activities of mitochondrial respiratory complexes I, III, IV, and V. The disorder is lethal, with no reported patients surviving past infancy (summary by Friederich et al., 2018). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation deficiency 41
MedGen UID:
1711853
Concept ID:
C5394236
Disease or Syndrome
Combined oxidative phosphorylation deficiency 42
MedGen UID:
1709379
Concept ID:
C5394237
Disease or Syndrome
Combined oxidative phosphorylation deficiency-42 (COXPD42) is an autosomal recessive metabolic disorder characterized by onset of cardiomyopathy, respiratory insufficiency, lactic metabolic acidosis, and anemia in the first months of life. Patient tissue shows variable impairment of mitochondrial oxidative phosphorylation affecting mtDNA-encoded subunits I, III, and IV. All reported affected infants have died in the first year of life (summary by Friederich et al., 2018). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Pseudo-TORCH syndrome 3
MedGen UID:
1708513
Concept ID:
C5394391
Disease or Syndrome
Pseudo-TORCH syndrome-3 (PTORCH3) is an autosomal recessive disorder of immune dysregulation and neuroinflammation apparent from early infancy. Affected individuals have developmental delay with acute episodes of fever and multisystemic organ involvement, including coagulopathy, elevated liver enzymes, and proteinuria, often associated with thrombotic microangiopathy. Brain imaging shows progressive intracranial calcifications, white matter abnormalities, and sometimes cerebral or cerebellar atrophy. Laboratory studies show abnormal elevation of interferon (IFN)-stimulated gene (ISG) transcripts consistent with a type I interferonopathy. The phenotype resembles the sequelae of intrauterine infection, but there is usually no evidence of an infectious agent. The disorder results from defects in negative regulation of the interferon immunologic pathway. Death in early childhood is common (summary by Duncan et al., 2019 and Gruber et al., 2020). For a discussion of genetic heterogeneity of PTORCH, see PTORCH1 (251290).
Vissers-Bodmer syndrome
MedGen UID:
1776566
Concept ID:
C5436647
Disease or Syndrome
Vissers-Bodmer syndrome (VIBOS) is characterized by global developmental delay with variably impaired intellectual development, speech delay, motor delay, and behavioral abnormalities apparent from infancy. The phenotype is highly variable: some individuals have only mild learning difficulties, whereas others have severe cognitive impairment with IQ in the 50s. Many patients have behavioral abnormalities, including autism spectrum disorder, ADD, ADHD, obsessive-compulsive disorder, and impulsivity. Other common features include growth impairment abnormalities, hypotonia, and distal skeletal defects, such as foot and hand deformities. Less common features include seizures, brain abnormalities on MRI, feeding problems, and joint hypermobility. Most individuals have dysmorphic facial features, but there is no recognizable gestalt (summary by Vissers et al., 2020).
Kohlschutter-Tonz syndrome-like
MedGen UID:
1781649
Concept ID:
C5543202
Disease or Syndrome
Den Hoed-de Boer-Voisin syndrome (DHDBV) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. The phenotype is reminiscent of Kohlschutter-Tonz syndrome (KTZS; 226750). More variable features of DHDBV include visual defects, behavioral abnormalities, and nonspecific involvement of other organ systems (summary by den Hoed et al., 2021).
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2
MedGen UID:
1778117
Concept ID:
C5543623
Disease or Syndrome
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2) is an autosomal recessive multisystemic disorder characterized by cholestatic hepatitis, poor feeding associated with poor overall growth, and hypoglycemia apparent from infancy. Most, but not all, patients have variable global developmental delay. Additional common features include sensorineural deafness, retinal abnormalities with visual defects, and hypotonia. Some patients have endocrine abnormalities, including hyperinsulinemic hypoglycemia, pancreatic dysfunction, hypothyroidism, and primary amenorrhea. Additional features may include hypertriglyceridemia, anemia, proteinuria, increased lactate, and recurrent infections. Brain imaging often shows dysmyelination, thin corpus callosum, cerebral atrophy, and white matter abnormalities. Although the clinical manifestations and severity of the disorder are highly variable, death in early childhood may occur (summary by Williams et al., 2019 and Zeiad et al., 2021). For a discussion of genetic heterogeneity of IMNEPD, see IMNEPD1 (616263).
DEGCAGS syndrome
MedGen UID:
1794177
Concept ID:
C5561967
Disease or Syndrome
DEGCAGS syndrome is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anemia or pancytopenia, and immunodeficiency with recurrent infections. Death in childhood may occur (summary by Bertoli-Avella et al., 2021).
Restrictive dermopathy 1
MedGen UID:
1812447
Concept ID:
C5676878
Disease or Syndrome
A restrictive dermopathy that has material basis in homozygous or compound heterozygous mutation in the ZMPSTE24 gene on chromosome 1p34.
Parkinsonism-dystonia 3, childhood-onset
MedGen UID:
1808365
Concept ID:
C5676913
Disease or Syndrome
Childhood-onset parkinsonism-dystonia-3 (PKDYS3) is an autosomal recessive neurodegenerative disorder with onset in infancy or early childhood. Affected individuals present with progressive movement abnormalities, including parkinsonism with tremor, dystonia, myoclonus ataxia, and hyperkinetic movements such as ballismus. The parkinsonism features may be responsive to treatment with levodopa, although many patients develop levodopa-induced dyskinesia. Some patients may have mild cognitive impairment or psychiatric disturbances (summary by Burke et al., 2018 and Skorvanek et al., 2022). For a discussion of genetic heterogeneity of PKDYS, see 613135.
Osteoporosis, childhood- or juvenile-onset, with developmental delay
MedGen UID:
1802083
Concept ID:
C5676992
Disease or Syndrome
Childhood- or juvenile-onset osteoporosis with developmental delay (OPDD) is characterized by evidence of osteopenia or osteoporosis, with recurrent fractures following minor trauma in some patients. Developmental delay is variable, and includes mild intellectual or learning disabilities as well as wide-based gait and/or gross motor delays. Microcephaly is present in some patients (Marom et al., 2021).
Paternal uniparental disomy of chromosome 14
MedGen UID:
1843450
Concept ID:
C5680251
Disease or Syndrome
Kagami-Ogata syndrome (KOS) is a rare imprinting disorder characterized prenatally by polyhydramnios, macrosomia, and placentomegaly. After birth, infants often have respiratory distress, feeding difficulties, and postnatal growth retardation. Thoracic abnormalities include small bell-shaped thorax, 'coat-hanger' ribs, narrow chest wall, and cardiac anomalies. Abdominal wall defects include omphalocele, diastasis recti, and inguinal hernias. Hepatoblastoma is present in some patients. Dysmorphic facial features include frontal bossing, depressed nasal bridge, hairy forehead, anteverted nares, micrognathia, and a short neck. Developmental findings include hypotonia, speech and/or motor delays, and normal to mildly impaired intellectual development (summary by Prasasya et al., 2020).
Dyskeratosis congenita, autosomal recessive 8
MedGen UID:
1824030
Concept ID:
C5774257
Disease or Syndrome
Autosomal recessive dyskeratosis congenita-8 (DKCB8) is characterized by progressive bone marrow failure affecting all lineages apparent from infancy or early childhood. More variable features may include poor growth, mild developmental delay, immunodeficiency, and gastrointestinal manifestations, such as esophageal stricture or inflammatory bowel disease. Some patients may have mucocutaneous features, including oral leukoplakia, nail dystrophy, or pigmentary skin abnormalities, although these features may be absent. Unlike patients with other forms of DKC, those with DKCB8 do not have shortened telomeres, although there is evidence of telomere instability. Hematopoietic stem cell transplant may be curative (Kermasson et al., 2022). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).

Professional guidelines

Recent clinical studies

Etiology

Roman A, Ramirez A, Fox NS
Am J Obstet Gynecol MFM 2022 Mar;4(2S):100551. Epub 2021 Dec 8 doi: 10.1016/j.ajogmf.2021.100551. PMID: 34896357
Barfield WD
Clin Perinatol 2018 Sep;45(3):565-577. doi: 10.1016/j.clp.2018.05.007. PMID: 30144856Free PMC Article
Ream MA, Lehwald L
Curr Neurol Neurosci Rep 2018 Jun 16;18(8):48. doi: 10.1007/s11910-018-0862-2. PMID: 29907917
Vogel JP, Chawanpaiboon S, Moller AB, Watananirun K, Bonet M, Lumbiganon P
Best Pract Res Clin Obstet Gynaecol 2018 Oct;52:3-12. Epub 2018 Apr 26 doi: 10.1016/j.bpobgyn.2018.04.003. PMID: 29779863
Goldenberg RL, Culhane JF, Iams JD, Romero R
Lancet 2008 Jan 5;371(9606):75-84. doi: 10.1016/S0140-6736(08)60074-4. PMID: 18177778Free PMC Article

Diagnosis

Obstet Gynecol 2021 Jun 1;137(6):e145-e162. doi: 10.1097/AOG.0000000000004397. PMID: 34011891
Griggs KM, Hrelic DA, Williams N, McEwen-Campbell M, Cypher R
MCN Am J Matern Child Nurs 2020 Nov/Dec;45(6):328-337. doi: 10.1097/NMC.0000000000000656. PMID: 33074911
Ville Y, Rozenberg P
Best Pract Res Clin Obstet Gynaecol 2018 Oct;52:23-32. Epub 2018 Jul 7 doi: 10.1016/j.bpobgyn.2018.05.002. PMID: 30309793
Glover AV, Manuck TA
Semin Fetal Neonatal Med 2018 Apr;23(2):126-132. Epub 2017 Dec 9 doi: 10.1016/j.siny.2017.11.007. PMID: 29229486Free PMC Article
Son M, Miller ES
Semin Perinatol 2017 Dec;41(8):445-451. Epub 2017 Sep 19 doi: 10.1053/j.semperi.2017.08.002. PMID: 28935263Free PMC Article

Therapy

Simões EAF, Madhi SA, Muller WJ, Atanasova V, Bosheva M, Cabañas F, Baca Cots M, Domachowske JB, Garcia-Garcia ML, Grantina I, Nguyen KA, Zar HJ, Berglind A, Cummings C, Griffin MP, Takas T, Yuan Y, Wählby Hamrén U, Leach A, Villafana T
Lancet Child Adolesc Health 2023 Mar;7(3):180-189. Epub 2023 Jan 9 doi: 10.1016/S2352-4642(22)00321-2. PMID: 36634694Free PMC Article
Oh C, Keats EC, Bhutta ZA
Nutrients 2020 Feb 14;12(2) doi: 10.3390/nu12020491. PMID: 32075071Free PMC Article
Smaill FM, Vazquez JC
Cochrane Database Syst Rev 2019 Nov 25;2019(11) doi: 10.1002/14651858.CD000490.pub4. PMID: 31765489Free PMC Article
Ville Y, Rozenberg P
Best Pract Res Clin Obstet Gynaecol 2018 Oct;52:23-32. Epub 2018 Jul 7 doi: 10.1016/j.bpobgyn.2018.05.002. PMID: 30309793
Khalifeh A, Berghella V
Am J Obstet Gynecol 2016 Dec;215(6):739-744.e1. doi: 10.1016/j.ajog.2016.07.019. PMID: 27889000

Prognosis

Cao G, Liu J, Liu M
JAMA Pediatr 2022 Aug 1;176(8):787-796. doi: 10.1001/jamapediatrics.2022.1622. PMID: 35639401Free PMC Article
Roman A, Ramirez A, Fox NS
Am J Obstet Gynecol MFM 2022 Mar;4(2S):100551. Epub 2021 Dec 8 doi: 10.1016/j.ajogmf.2021.100551. PMID: 34896357
Delnord M, Zeitlin J
Semin Fetal Neonatal Med 2019 Feb;24(1):3-10. Epub 2018 Sep 18 doi: 10.1016/j.siny.2018.09.001. PMID: 30309813
Glass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ
Anesth Analg 2015 Jun;120(6):1337-51. doi: 10.1213/ANE.0000000000000705. PMID: 25988638Free PMC Article
Platt MJ
Public Health 2014 May;128(5):399-403. Epub 2014 May 1 doi: 10.1016/j.puhe.2014.03.010. PMID: 24794180

Clinical prediction guides

Stepan H, Galindo A, Hund M, Schlembach D, Sillman J, Surbek D, Vatish M
Ultrasound Obstet Gynecol 2023 Feb;61(2):168-180. doi: 10.1002/uog.26032. PMID: 35816445
Suff N, Story L, Shennan A
Semin Fetal Neonatal Med 2019 Feb;24(1):27-32. Epub 2018 Sep 28 doi: 10.1016/j.siny.2018.09.006. PMID: 30337215
Oskovi Kaplan ZA, Ozgu-Erdinc AS
J Pregnancy 2018;2018:8367571. Epub 2018 Oct 10 doi: 10.1155/2018/8367571. PMID: 30405914Free PMC Article
Boelig RC, Berghella V
J Perinat Med 2018 Jul 26;46(5):455-456. doi: 10.1515/jpm-2018-0160. PMID: 29794253
Son M, Miller ES
Semin Perinatol 2017 Dec;41(8):445-451. Epub 2017 Sep 19 doi: 10.1053/j.semperi.2017.08.002. PMID: 28935263Free PMC Article

Recent systematic reviews

Conde-Agudelo A, Romero R
Am J Obstet Gynecol 2022 Sep;227(3):440-461.e2. Epub 2022 Apr 20 doi: 10.1016/j.ajog.2022.04.023. PMID: 35460628Free PMC Article
Nielsen OH, Gubatan JM, Juhl CB, Streett SE, Maxwell C
Clin Gastroenterol Hepatol 2022 Jan;20(1):74-87.e3. Epub 2020 Sep 12 doi: 10.1016/j.cgh.2020.09.021. PMID: 32931960
Jang H, Patoine A, Wu TT, Castillo DA, Xiao J
Sci Rep 2021 Aug 19;11(1):16870. doi: 10.1038/s41598-021-96495-1. PMID: 34413437Free PMC Article
Azevedo WF, Diniz MB, Fonseca ES, Azevedo LM, Evangelista CB
Einstein (Sao Paulo) 2015 Oct-Dec;13(4):618-26. Epub 2015 Jun 9 doi: 10.1590/S1679-45082015RW3127. PMID: 26061075Free PMC Article
Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic VD
Clin J Am Soc Nephrol 2010 Nov;5(11):2060-8. Epub 2010 Aug 5 doi: 10.2215/CJN.00240110. PMID: 20688887Free PMC Article

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    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2023
      ACMG ACT, FA + Low/Moderate Barts Hb, FAB2, FAB1 Alpha Thalassemia: Silent carrier and alpha thalassemia trait, 2023
    • ACMG Algorithm, 2023
      ACMG Algorithm, Hemoglobin FA + Barts: Low/Moderate Barts Alpha Thalassemia Screening Result (FAB2; FAB1), 2023
    • ACMG ACT, 2023
      ACMG ACT, FA + High Barts Hb (>20-25% Barts) or FAB3), Alpha (a) Thalassemia: Hb H Disease
    • ACMG Algorithm, 2023
      ACMG Algorithm, Hemoglobin FA + Barts: High Barts Alpha Thalassemia Screening Result (FAB3; FA + Barts > 20-25%), 2023

    Consumer resources

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