Japanese siblings with cartilage-hair hypoplasia exhibiting different severity.

Cartilage-hair hypoplasia (CHH) is a rare disorder characterized by skeletal dysplasia, short stature, hair hypoplasia, immunodeficiency, and increased incidences of anemia, Hirschsprung disease, and malignancy.1 This condition is caused by a mutation in the non-coding ribonuclease mitochondrial RNA processing gene (RMRP) and exhibits an autosomal recessive inheritance.1 In Japan, CHH is often diagnosed through workup of short stature. We encountered two siblings diagnosed with CHH during T-cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle newborn screening followed by next-generation sequencing (NGS) for severe combined immunodeficiency (SCID).2 Genetic analysis revealed a novel compound heterozygous variant in RMRP. Here, we report the detailed clinical features and relationship between the variants and clinical symptoms of the siblings. The older brother was born via normal delivery at 37 weeks and 4 days of gestation. During the prenatal period, he had shortened limbs. His birthweight was 2165 g (−1.75 SD), height was 44 cm (−1.72 SD), head circumference was 32 cm (−0.64 SD), and chest circumference was 28 cm. He was diagnosed with small for gestational age. He underwent newborn screening for SCID, which showed a low TREC value (15 copies/μL; reference range >31 copies/μL).2 Growth failure was observed at 4 months of age (Figure 1a). He had light-colored hypoplastic hair (Figure 1b). His psychomotor development was normal. The younger brother was also born via normal delivery at 39 weeks and 1 day of gestation, and, similar to his older brother, he had shortened limbs during the prenatal period. His birthweight was 2740 g (−1.05 SD), height was 43.4 cm (−2.73 SD), head circumference was 34 cm (+0.59 SD), and chest circumference was 32.5 cm. He underwent newborn screening for SCID, which showed a low TREC value (8 copies/μL).2 He had a low number of CD3+ cells and CD4 + CD45RA+ cells than his older brother. Cellular immunodeficiency was of concern, and live vaccination was avoided.2 No clinical evidence of frequent infection had been observed so far. He exhibited poorer growth than his older brother (Figure 1c), had light-colored curled hypoplastic hair (Figure 1d), and began walking at 10 months of age. Both of their parents had black hair. Genetic analysis of the siblings revealed the same variants in RMRP. One variant, NR_003051.3:n.67G >C, is a novel variant classified as likely to be pathogenic by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria.3 This variant is documented only in gnomAD with a frequency of 0.00007. The other variant, NR_003051.3:n.219A >G, was previously reported as pathogenic. The variants are compound heterozygotes. The patients were first detected during newborn screening for SCID, followed by genetic analysis, which confirmed a diagnosis of CHH.2 The patients were also clinically diagnosed with CHH, due to observed short stature and hair abnormalities. Both siblings had compound heterozygosity variants, and the parents were identified as carriers of the RMRP variant. Although the siblings had the same variants, the younger brother demonstrated more severe symptoms, including more profound dwarfism, and more severe immunological abnormalities than those of his older brother. Genotype does not necessarily correlate with clinical severity and highly variable clinical phenotype has been described in identical RMRP variants, even in siblings.1 However, the clinical severity is correlated with the degree of short stature.4 The fact that the younger brother, who was smaller than the older brother, demonstrated more severe symptoms, is consistent with the clinical characteristics of RMRP mutations.4 Genetic analysis was carried out in our patients. Targeted NGS was first performed to detect 349 genes that cause immunodeficiency. Thereafter the candidate was validated with Sanger sequencing.2 This is the first case report of CHH detected during newborn screening for SCID in Japan.2 In Japan, CHH is often diagnosed through workup of short stature. In countries where newborn screening for SCID is performed, CHH is often diagnosed from this.5 In recent years, newborn screening for SCID has been performed only in some parts of Japan. More patients similar to ours will be diagnosed if newborn screening for SCID is widely performed in Japan. Naonori Kumagai wrote the manuscript; Yusuke Funato collected the clinical data of the patients; Manabu Wakamatsu and Hideki Muramatsu performed newborn screening and genetic analysis; Haruo Mizuno critically reviewed the manuscript. Informed consent was obtained from the patients' parents for the publication of this report. We would like to thank Editage (www.editage.com) for the English language editing and Professor Hiroki Kurahashi (Fujita Health University) for interpretation of genetic analysis. The authors declare no conflict of interest.