A very rare genetic disorder with characteristics of the following congenital malformations: hydrocephalus (due to Dandy-Walker anomaly), cleft palate and severe joint contractures. Less than 20 cases have been reported in the literature. The fingers are thin with absent knuckles and reduced creases over the joints and patients show an inability to make a full fist. Additional findings may include deformed ears, ptosis, an inability to open the mouth fully, heart defects, and clubfoot. There are currently no human genes associated with this disease.

The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005).

Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV) in combination with abnormalities of the ribs, is characterized clinically by: a short trunk in proportion to height; short neck; non-progressive mild scoliosis in most affected individuals, and occasionally, more significant scoliosis. Respiratory function in neonates may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development; however, even then life-threatening complications can occur, especially pulmonary hypertension in children with severely restricted lung capacity from birth. Males with SCDO appear to be at increased risk for inguinal hernia.

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord.

Immunodeficiency-59 and hypoglycemia (IMD59) is an autosomal recessive primary immunologic disorder characterized by combined immunodeficiency and recurrent septic infections of the respiratory tract, skin, and mucous membranes, as well as disturbed glucose metabolism. Granulocytopenia and B-cell and dendritic cell deficiency are present (Haapaniemi et al., 2017).

Mandibulofacial dysostosis with microcephaly (MFDM) is characterized by malar and mandibular hypoplasia, microcephaly (congenital or postnatal onset), intellectual disability (mild, moderate, or severe), malformations of the external ear, and hearing loss that is typically conductive. Associated craniofacial malformations may include cleft palate, choanal atresia, zygomatic arch cleft (identified on cranial CT scan), and facial asymmetry. Other relatively common findings (present in 25%-35% of individuals) can include cardiac anomalies, thumb anomalies, esophageal atresia/tracheoesophageal fistula, short stature, spine anomalies, and epilepsy.

Koolen-de Vries syndrome (KdVS) is characterized by developmental delay / intellectual disability, neonatal/childhood hypotonia, dysmorphisms, congenital malformations, and behavioral features. Psychomotor developmental delay is noted in all individuals from an early age. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability. Other findings include speech and language delay (100%), epilepsy (~33%), congenital heart defects (25%-50%), renal and urologic anomalies (25%-50%), and cryptorchidism (71% of males). Behavior in most is described as friendly, amiable, and cooperative.

Christianson syndrome (referred to as CS in this GeneReview), an X-linked disorder, is characterized in males by cognitive dysfunction, behavioral disorder, and neurologic findings (e.g., seizures, ataxia, postnatal microcephaly, and eye movement abnormalities). Males with CS typically present with developmental delay, later meeting criteria for severe intellectual disability (ID). Behaviorally, autism spectrum disorder and hyperactivity are common, and may resemble the behaviors observed in Angelman syndrome. Hypotonia and oropharyngeal dysphagia in infancy may result in failure to thrive. Seizures, typically beginning before age three years, can include infantile spasms and tonic, tonic-clonic, myoclonic, and atonic seizures. Subsequently, regression (e.g., loss of ambulation and ability to feed independently) may occur. Manifestations in heterozygous females range from asymptomatic to mild ID and/or behavioral issues.

Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the TRAPPC9 gene.

17q23.1q23.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, microcephaly, short stature, heart defects and limb abnormalities.

A heterozygous deletion of chromosome 15q11.2 may increase the susceptibility to neuropsychiatric or neurodevelopmental problems, including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, and possibly seizures (summary by Doornbos et al., 2009 and Burnside et al., 2011). See also chromosome 15q11.2 duplication syndrome (608636).

NEDDFL is a neurodevelopmental disorder characterized by delayed psychomotor development and impaired intellectual development, poor growth with small head size, dysmorphic facial features, and mild abnormalities of the hands and feet (summary by Stankiewicz et al., 2017).

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.

Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome is an autosomal recessive disorder with a highly variable phenotype. Although all patients have polymicrogyria and other variable structural brain anomalies on imaging, only some show developmental delay and/or seizures. Similarly, only some patients have connective tissue defects that particularly affect the vascular system and can result in early death (summary by Vandervore et al., 2017).

Neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) is characterized by global developmental delay apparent from infancy or early childhood, resulting in mildly delayed walking, variably impaired intellectual development, and poor or absent speech. Additional features may include hypotonia, spasticity, or ataxia. About half of patients have abnormal findings on brain imaging, including cerebral or cerebellar atrophy, loss of white matter volume, thin corpus callosum, and perisylvian polymicrogyria. Seizures are not a prominent finding, and although some patients may have nonspecific dysmorphic facial features, there is no common or consistent gestalt (summary by Platzer et al., 2019).

Coffin-Siris syndrome-12 (CSS12) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, speech and language delay, and behavioral abnormalities, such as autism or hyperactivity. Affected individuals may have hypotonia and poor feeding in infancy. There are variable dysmorphic facial features, although most patients do not have the classic hypoplastic fifth digit/nail abnormalities that are often observed in other forms of CSS (Barish et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).

Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022).

Chilton-Okur-Chung neurodevelopmental syndrome (CHOCNS) is characterized mainly by global developmental delay with variably impaired intellectual development and occasional speech delay. Most patients have behavioral abnormalities, including autism spectrum disorder, ADHD, and aggression. About half of patients have dysmorphic facial features, and about half have nonspecific brain abnormalities, including thin corpus callosum. Rare involvement of other organ systems may be present. At least 1 child with normal development at age 2.5 years has been reported (Chilton et al., 2020).

Autosomal recessive intellectual developmental disorder-79 (MRT79) is characterized by global developmental delay apparent from infancy. Affected individuals have mildly delayed walking with an ataxic gait and severely impaired intellectual development with poor or absent speech. Additional features may include postnatal microcephaly and dysmorphic features (Van Bergen et al., 2022).