Short stature-brachydactyly-obesity-global developmental delay syndrome (ORPHA:464288)
A rare genetic, multiple congenital anomalies syndrome characterized by short stature, hand brachydactyly with hypoplastic distal phalanges, global development delay, intellectual disability, and more variably seizures, obesity, and craniofacial dysmorphism that includes microcephaly, high forehead, flat face, hypertelorism, deep set eyes, flat nasal bridge, averted nostrils, long philtrum, thin lip vermilion, and short neck.
Epidemiology
Less than 15 cases have been reported in the literature to date.
Clinical description
Initial presentation can be with intrauterine growth retardation or low birthweight. Symptoms of global development delay includes hypotonia, delay in achieving independent sitting and walking and marked language delay. Intellectual disability ranges from mild to severe. Ocular anomalies include strabismus, coloboma, dacryostenosis and blue sclera. Obesity develops in late infancy. Seizures can present in infancy or childhood, are phenotypically variable including absences and febrile convulsions. In addition to hypoplasia of the distal phalanges, the 4th and 5th fingers may show a marked reduction in metacarpal length; brachydactyly of the feet may also be present. Other variable features reported include bilateral absent patellae, sensorineural hearing loss, feeding difficulties in early infancy, dysphagia, kyphosis, eczema, cryptorchidism and laryngomalacia.
Etiology
The malformation is due to a loss of function in the enzyme protein arginine N-methyltransferase 7 (encoded by PRMT7, 16q22.1) resulting in decreased levels of protein arginine methylation.
Diagnostic methods
Diagnosis is based on presentation of clinical features, and can be confirmed by genetic testing.
Differential diagnosis
Differential diagnosis include Albright hereditary osteodystrophies with pseudohypoparathyroidism.
Antenatal diagnosis
There is no definitive antenatal diagnosis available, however ultrasound may show intrauterine growth retardation which should be investigated further.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Given that patients with biallelic mutations in PRMT7 present with a spectrum of multisystemic involvement, medical multidisciplinary follow-up is needed. Neurological follow up is indicated with special attention to seizures. Hearing evaluation is recommended at time of diagnosis. Surveillance should also include frequent monitoring of growth and development; regular ophthalmological follow up. Hormonal and phosphocalcic metabolism alterations have been reported in two patients so far, so this should also be tested.
Prognosis
Developmental delay and intellectual disability had been reported in all patients to date, with variable in severity. Language is more severely affected when hearing impairment is present.

                            Last update: 
                            October 2020


                            - Expert reviewer(s): 
                            Dr Irene VALENZUELA PALAFOLL | ITHACA*


                                * European Reference Network