Pycnodysostosis is characterized by short-limbed short stature, typical facial appearance (convex nasal ridge and small jaw with obtuse mandibular angle), osteosclerosis with increased bone fragility, acroosteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. In affected individuals, the facial features become more prominent with age, likely due to progressive acroosteolysis of the facial bones, but can usually be appreciated from early childhood, particularly the small jaw and convex nasal ridge. Additional features include dental and nail anomalies. Intelligence is typically normal with mild psychomotor difficulties reported in some individuals.

Pyle disease is characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility. Fractures are common in Pyle disease, and fracture lines usually go through the abnormally wide metaphyses, revealing their fragility (summary by Kiper et al., 2016).

Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty.

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.

Andersen-Tawil syndrome (ATS) is characterized by a triad of: episodic flaccid muscle weakness (i.e., periodic paralysis); ventricular arrhythmias and prolonged QT interval; and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) have been described.

Eiken syndrome (EKNS) is an autosomal recessive skeletal dysplasia characterized by delayed ossification of bones, epiphyseal dysplasia, and bone remodeling abnormalities. Type A1 brachydactyly (see 112500), supernumerary epiphyses of proximal phalanges and metacarpals, and failure of eruption of primary teeth have also been described. Defining radiologic features include delayed ossification of epiphyses and primary ossification centers of short tubular bones, modeling abnormalities of tubular bones, and angel-shaped phalanges (Jacob et al., 2019). See 603740 for a disorder with similar radiologic features.

Oculofaciocardiodental (OFCD) syndrome is a condition that affects the development of the eyes (oculo-), facial features (facio-), heart (cardio-) and teeth (dental). This condition occurs only in females.\n\nThe eye abnormalities associated with OFCD syndrome can affect one or both eyes. Many people with this condition are born with eyeballs that are abnormally small (microphthalmia). Other eye problems can include clouding of the lens (cataract) and a higher risk of glaucoma, an eye disease that increases the pressure in the eye. These abnormalities can lead to vision loss or blindness.\n\nPeople with OFCD syndrome often have a long, narrow face with distinctive facial features, including deep-set eyes and a broad nasal tip that is divided by a cleft. Some affected people have an opening in the roof of the mouth called a cleft palate.\n\nHeart defects are another common feature of OFCD syndrome. Babies with this condition may be born with a hole between two chambers of the heart (an atrial or ventricular septal defect) or a leak in one of the valves that controls blood flow through the heart (mitral valve prolapse).\n\nTeeth with very large roots (radiculomegaly) are characteristic of OFCD syndrome. Additional dental abnormalities can include delayed loss of primary (baby) teeth, missing or abnormally small teeth, misaligned teeth, and defective tooth enamel.

Osteopetrosis is a bone disease that makes bone tissue abnormally compact and dense and also prone to breakage (fracture). Researchers have described several major types of osteopetrosis, which are usually distinguished by their pattern of inheritance: autosomal dominant or autosomal recessive. The different types of the disorder can also be distinguished by the severity of their signs and symptoms.\n\nAutosomal dominant osteopetrosis (ADO), which is also called Albers-Schönberg disease, is typically the mildest type of the disorder. Some affected individuals have no symptoms. In affected people with no symptoms, the unusually dense bones may be discovered by accident when an x-ray is done for another reason. \n\nIn individuals with ADO who develop signs and symptoms, the major features of the condition include multiple bone fractures after minor injury, abnormal side-to-side curvature of the spine (scoliosis) or other spinal abnormalities, arthritis in the hips, and a bone infection called osteomyelitis. These problems usually become apparent in late childhood or adolescence.\n\nAutosomal recessive osteopetrosis (ARO) is a more severe form of the disorder that becomes apparent in early infancy. Affected individuals have a high risk of bone fracture resulting from seemingly minor bumps and falls. Their abnormally dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial muscles. Dense bones can also impair the function of bone marrow, preventing it from producing new blood cells and immune system cells. As a result, people with severe osteopetrosis are at risk of abnormal bleeding, a shortage of red blood cells (anemia), and recurrent infections. In the most severe cases, these bone marrow abnormalities can be life-threatening in infancy or early childhood.\n\nOther features of autosomal recessive osteopetrosis can include slow growth and short stature, dental abnormalities, and an enlarged liver and spleen (hepatosplenomegaly). Depending on the genetic changes involved, people with severe osteopetrosis can also have brain abnormalities, intellectual disability, or recurrent seizures (epilepsy).\n\nA few individuals have been diagnosed with intermediate autosomal osteopetrosis (IAO), a form of the disorder that can have either an autosomal dominant or an autosomal recessive pattern of inheritance. The signs and symptoms of this condition become noticeable in childhood and include an increased risk of bone fracture and anemia. People with this form of the disorder typically do not have life-threatening bone marrow abnormalities. However, some affected individuals have had abnormal calcium deposits (calcifications) in the brain, intellectual disability, and a form of kidney disease called renal tubular acidosis.

Primary failure of tooth eruption (PFE) is an autosomal dominant disorder in which nonankylosed posterior teeth fail to move along the eruption path cleared for them, resulting in a posterior open bite. Failure of affected teeth to respond to orthodontic force is a key characteristic (summary by Frazier-Bowers et al., 2007). See also 157950 and 273050 for phenotypes with shared features of PFE.

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.

Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly), genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora), dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality. A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss, in addition to the typical features described above.

Carpenter syndrome is a rare autosomal recessive disorder with the cardinal features of acrocephaly with variable synostosis of the sagittal, lambdoid, and coronal sutures; peculiar facies; brachydactyly of the hands with syndactyly; preaxial polydactyly and syndactyly of the feet; congenital heart defects; growth retardation; mental retardation; hypogenitalism; and obesity. In addition, cerebral malformations, oral and dental abnormalities, coxa valga, genu valgum, hydronephrosis, precocious puberty, and hearing loss may be observed (summary by Altunhan et al., 2011). Genetic Heterogeneity of Carpenter Syndrome Carpenter syndrome-2 (CRPT2; 614976), in which the features of Carpenter syndrome are sometimes associated with defective lateralization, is caused by mutation in the MEGF8 gene (604267).

STAT3 hyper IgE syndrome (STAT3-HIES) is a primary immune deficiency syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency.

EDFAOB is characterized by linear hypopigmentation and craniofacial asymmetry in association with ocular, dental, and acral anomalies. Brain imaging has revealed some abnormalities, including diffuse cystic leukoencephalopathy and mildly enlarged lateral ventricles, but patients show no intellectual or neurologic impairment (Vabres et al., 2019).

Hyper-IgE syndrome-4A with recurrent infections (HIES4A) is an autosomal dominant immunologic disorder characterized by recurrent, mainly sinopulmonary infections associated with increased serum IgE. The phenotype is variable, even within families. Some patients have onset of symptoms in early childhood and develop complications, including bronchiectasis or hemoptysis, whereas others have later onset of less severe infections. Immunologic workup usually shows normal leukocyte levels, although some patients may demonstrate alterations in lymphocyte subsets, including T cells. Affected individuals also have variable skeletal abnormalities, including high-arched palate, hyperextensible joints, scoliosis, and bone fractures. The IL6ST mutations are loss-of-function, although the truncated mutant proteins are expressed and interfere with the wildtype protein in a dominant-negative manner by disrupting IL6 (147620) and IL11 (147681) signaling (summary by Beziat et al., 2020). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).

Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (MNDLFH) is characterized by clinically significant pharyngeal lymphoid hypertrophy, with adenoid overgrowth, frequent upper airway infections, and sleep apnea. Macrocephaly without structural brain abnormalities is present, and patients exhibit increased weight for height as well as delayed gross motor and impaired intellectual development; autistic features and attention-deficit hyperactivity disorder have also been reported. An increased fraction of fetal hemoglobin has been observed in some patients (Ohishi et al., 2020; von der Lippe et al., 2022).