Coarse facial features

Mucolipidosis type-II (ML-II) is an ultra-rare disorder caused by deficiency of N-acetylglucosaminyl-1-phosphotransferase enzyme due to biallelic pathogenic variants in GNPTAB gene. There are a few known about the natural history of ML-II. In this study, we presented the natural course of 24 patients diagnosed with ML-II. Mean age at diagnosis was 9.3 ± 5.7 months. All patients had coarse face, developmental delay, and hypotonia. The mean survival time was 3.01 ± 1.4 years. The oldest patient was 6.5 years old. Twelve patients died due to lung infection and respiratory failure. We observed early and significant radiological findings of ML-II were different from typical dysostosis multiplex such as femoral cloaking, rickets-like changes, and talocalcaneal stippling. These are significant findings observed in the fetal or newborn period which is considered to be highly characteristic of ML-II and disappears in the first year. Cloaking, rickets-like changes, and stippling were not observed in patients older than three months of age and this suggests that these findings disappear within the first year. These radiological features can be used as important clues for diagnosis. We detected eight different pathogenic variants in GNPTAB gene, three of them were novel.

Coffin-Siris Syndrome (CSS, MIM 135900) is now a well-described genetic condition caused by pathogenic variants in the Bromocriptine activating factor (BAF) complex, including ARID1B, ARID1A, ARID2, SMARCA4, SMARCE1, SMARCB1, SOX11, SMARCC2, DPF2, and more recently, BICRA. Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties, hypotonia, organ-system anomalies, and learning and developmental differences. The classic finding of fifth digit hypo- or aplasia is seen variably. ARID2, previously described, is one of the less frequently observed gene changes in CSS. Although individuals with ARID2 have been reported to have classic features of CSS including hypertrichosis, coarse facial features, short stature, and fifth digit anomalies, as with many of the other CSS genes, there appears to be a spectrum of phenotypes. We report here a cohort of 17 individuals with ARID2 variants from the Coffin-Siris/BAF clinical registry and detail their medical challenges as well as developmental progress. Feeding difficulties, hypotonia, and short stature occur often, and hip dysplasia appears to occur more often than with other genes, however more severe medical challenges such as significant brain and cardiac malformations are rarer. Individuals appear to have mild to moderate intellectual impairment and may carry additional diagnoses such as ADHD. Further phenotypic description of this gene will aid clinicians caring for individuals with this rarer form of CSS.

Mucopolysaccharidosis type VII (MPS VII) is an ultra-rare, life-threatening, progressive disease caused by genetic mutations that affect lysosomal storage/function. MPS VII has an estimated prevalence of <1:1,000,000 and accounts for <3% of all MPS diagnoses. Given the rarity of MPS VII, comprehensive information on the disease is limited and we present a review of the current understanding. In MPS VII, intracellular glycosaminoglycans accumulate due to a deficiency in the lysosomal enzyme that is responsible for their degradation, β-glucuronidase, which is encoded by the GUSB gene. MPS VII has a heterogeneous presentation. Features can manifest across multiple systems and can vary in severity, age of onset and progression. The single most distinguishing clinical feature of MPS VII is non-immune hydrops fetalis (NIHF), which presents during pregnancy. MPS VII usually presents within one month of life and become more prominent at 3 to 4 years of age; key features are skeletal deformities, hepatosplenomegaly, coarse facies, and cognitive impairment, although phenotypic variation is a hallmark. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy with vestronidase alfa. Care should be individualized for each patient. Development of consensus guidelines for MPS VII management and treatment is needed, as consolidation of expert knowledge and experience (for example, through the MPS VII Disease Monitoring Program) may provide a significant positive impact to patients.