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Microcephalic cortical malformations-short stature due to RTTN deficiency
Disease definition
A rare, genetic, neurodevelopmental disorder with primordial microcephaly characterized by primary microcephaly, moderate to severe intellectual disability, and global developmental delay. Variable brain malformations are common ranging from simplified gyration, to cortical malformations such as pachygyria, polymicrogyria, reduced sulcation and midline defects. Craniofacial dysmorphism (e.g. sloping forehead, high and broad nasal bridge) are related to the primary microcephaly. Short stature is frequently observed, and may be severe.
ORPHA:468631
Classification level: Disorder- Synonym(s): -
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Neonatal, Infancy
- ICD-10: Q02
- OMIM: 614833
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
Summary
Epidemiology
To date, approximately 30 cases with identified RTTN mutations have been reported in the scientific and medical literature. Males and females are equally affected.
Clinical description
Presentation can be in utero or at birth with congenital microcephaly. Cortical malformations are common with a broad spectrum ranging from polymicrogyria-like dysgyric cortex to severe congenital microcephaly with large interhemispheric cysts. The cortical malformation is often predominant in frontal regions, suggesting elective underdevelopment of frontal lobes. The neurological problems include severe cognitive, motor and speech delay and only rarely seizures. The clinical severity correlates with the extension of the migration disorder and with the extent of microcephaly. Variable congenital anomalies occur, including eye anomalies (microphthalmia, abnormal orbitae, ankyloblepharon, optic hypoplasia), pituitary failure (growth and endocrine anomalies), urogenital malformations (cryptorchidism, micropenis, double uterus), kidney defect (agenesis, ectopy, pyelocaliectasis), skeletal anomalies (kyphoscoliosis, hip dysplasia), and heart defects. Short stature is variable and can be severe.
Etiology
Germline biallelic variants in RTTN (18q22.2) are responsible for the disease.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by genetic testing: exome sequencing or panel-based exome sequencing.
Differential diagnosis
Differential diagnosis is of other causes of autosomal-recessive non-syndromic primary microcephaly with primary dwarfism or short stature.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive; genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Supportive care includes physical therapy to manage the complications of spasticity, occupational therapy, and speech therapy based on individual needs. Nutritional needs commonly require nasogastric tube feeding, followed eventually by gastrostomy tube placement. Seizures are treated with antiepileptic drugs based on the specific seizure type.
Prognosis
The prognosis of these severe neurodevelopmental diseases is poor, with multiple disabilities and the subsequent complications (respiratory, nutritional, orthopedic) in almost all cases. For patients with severe cortical malformations (lissencephalies, polymicrogyria-like cortical dysplasia), it is usually appropriate to discuss the level of care to be provided in the event of a severe intercurrent illness. No data are available on the quality of life or life expectancy of patients with RTTN mutations.
A summary on this disease is available in Italiano (2020) Español (2021) Français (2021) Nederlands (2021) Polski ()
Additional information