Search for a rare disease
Other search option(s)
Goldberg-Shprintzen megacolon syndrome
A rare multiple congenital anomalies/dysmorphic syndrome characterized by Hirschsprung disease, facial dysmorphism (sloping forehead, high arched eyebrows, long eyelashes, telecanthus/hypertelorism, ptosis, prominent ears, thick earlobes, prominent nasal bridge, thick philtrum, everted lower lip vermillion and pointed chin), global developmental delay, intellectual disability and variable cerebral abnormalities (focal or generalized polymicrogyria, or hypoplastic corpus callosum).
ORPHA:66629Classification level: Disorder
Worldwide prevalence is less than 1/1,000,000; to date 24 cases have been described in the scientific and medical literature.
Disease onset is typically in the neonatal period with microcephaly and Hirschsprung disease. The clinical spectrum of Hirschsprung disease is broad, ranging from chronic constipation to life-threatening intestinal obstruction in neonates. Facial dysmorphism is present at birth but becomes more evident later on. Additional dysmorphic features may include maxillary hypoplasia, hypodontia, high arched palate, short neck, small hands, brachydactyly, fifth finger clinodactyly, fetal finger pads and flatfoot. Hypotonia, severe global developmental delay (with greatest impairment in expressive language skills) and moderate to severe intellectual disability are constant features. Cerebral magnetic resonance imaging reveals abnormalities in half of patients and may include polymicrogyria, corpus callosum hypoplasia, or subarachnoid space enlargement. Other highly variable features include ocular abnormalities (e.g. hyperopia, bilateral megalocornea), congenital heart defects (such as ventricular septal defects, aortic valve incompetence), urogenital abnormalities (incl. cryptorchidism, vesicoureteral reflux, multicystic renal dysplasia), skeletal involvement (e.g. short stature, scoliosis, femoral neck anteversion), and recurrent respiratory infections.
Disease is caused by bi-allelic mutations in KIF1BP (10q21.3-q22.1), encoding kinesin family member 1 binding protein. KIF1BP loss of function disrupts cytoskeletal homeostasis.
Diagnosis is based on clinical presentation of the typical features and should be confirmed with genetic testing. Hirschsprung disease is confirmed by rectal biopsy with histological findings of aganglionosis of the submucosal plexus.
Main differential diagnoses include Mowat-Wilson (MWS) and Baraitser-Winter syndromes. Different facial characteristics (thick, horizontal eyebrows and uplifted earlobes with a central depression), presence of seizures and hypospadias, and absence of polymicrogyria and oligodontia distinguish MWS. Key overlapping features with Baraitser-Winter syndrome include intellectual disability, microcephaly, congenital ptosis, high-arched eyebrows, ocular coloboma and short stature; however, Hirschsprung disease, congenital heart defects, and urogenital malformations have not been reported in this syndrome.
Genetic prenatal diagnosis is possible if bi-allelic mutations have previously been identified in the family. In absence of a familial case, diagnostic antenatal ultrasound is challenging. Antenatal detection of brain developmental anomalies, microcephaly, growth retardation and/or hyperechogenic gut are suspicious for the disease but must be confirmed by genetic testing.
The pattern of inheritance is autosomal recessive. For parents of an affected child the sibling-recurrence risk is 25%.
Management and treatment
Multidisciplinary medical care and preventive actions, such as treatment of cardiac, ocular, urogenital and skeletal issues and Hirschsprung disease, are required. Developmental assessments are needed to tailor medical care to individual needs and to increase the individual's quality of life.
Little information is available about the long-term outlook for individuals with Goldberg-Schprintzen megacolon syndrome. Quality of life and life expectancy depend on the presence and severity of birth defects.