RMRP-related short stature: A report of six additional Japanese individuals with cartilage hair hypoplasia and literature review.

Biallelic pathogenic variants in RMRP, the gene encoding the RNA component of RNase mitochondrial RNA processing enzyme complex, have been reported in individuals with cartilage hair hypoplasia (CHH). CHH is prevalent in Finnish and Amish populations due to a founder pathogenic variant, n.71A > G. Based on the manifestations in the Finnish and Amish individuals, the hallmarks of CHH are prenatal-onset growth failure, metaphyseal dysplasia, hair hypoplasia, immunodeficiency, and other extraskeletal manifestations. Herein, we report six Japanese individuals with CHH from four families. All probands presented with moderate short stature with mild metaphyseal dysplasia or brachydactyly. One of them had hair hypoplasia and the other immunodeficiency. By contrast, the affected siblings of two families showed only mild short stature. We also reviewed all previously reported 13 Japanese individuals. No n.71A > G allele was detected. The proportions of Japanese versus Finnish individuals were 0% versus 70% for birth length < -2.0 SD, 84% versus 100% for metaphyseal dysplasia and 26% versus 88% for hair hypoplasia. Milder manifestations in the Japanese individuals may be related to the difference of genotypes. The mildest form of CHH phenotypes is mild short stature without overt skeletal alteration or extraskeletal manifestation and can be termed "RMRP-related short stature".

Znrf3 exon 2 deletion mice do not recapitulate congenital adrenal hypoplasia.

Wnt/ß-catenin signaling is essential for adrenocortical development. Zinc and ring finger 3 (ZNRF3), an E3 ubiquitin ligase that attenuates Wnt/ß-catenin signaling, is negatively regulated by R-spondin via an extracellular domain that is partially encoded by exon 2 of ZNRF3. We recently identified ZNRF3 exon 2 deletions in three individuals with congenital adrenal hypoplasia. ZNRF3 exon 2 deletion impairs R-spondin binding, thereby attenuating ß-catenin expression and eventually leading to the development of congenital adrenal hypoplasia. To elucidate the influence of ZNRF3/Znrf3 exon 2 deletion on adrenocortical development, we generated homozygous Znrf3 exon 2 deletion (Znrf3Δ2/Δ2) mice. Whereas the adrenal glands of Znrf3Δ2/Δ2 mice did not show gross morphological changes at birth, moderate hyperplasia of the zona fasciculata (ZF), dispersed medulla arrangement, and a radially spreading zone with macrophage infiltration between the ZF and medulla were observed at 6 weeks of age. 20α-hydroxysteroid dehydrogenase, a marker of the adrenal X-zone, was hardly detected by immunostaining, and gene expression was significantly downregulated. The number of activated ß-catenin-positive cells decreased in the zona glomerulosa, consistent with the results of in situ hybridization for Axin2, a Wnt/ß-catenin target gene. Plasma ACTH and serum corticosterone levels in Znrf3Δ2/Δ2 mice did not differ significantly from those in wild-type mice. These results show a species-specific difference in the effects of ZNRF3/Znrf3 exon 2 deletions in humans and mice; Znrf3Δ2/Δ2 mice do not develop congenital adrenal hypoplasia but instead exhibit moderate ZF hyperplasia, dispersed medulla arrangement, X-zone dysplasia, and macrophage infiltration occurred in the inner cortex.

A novel mutation in the ACAN gene in a family with autosomal dominant short stature and intervertebral disc disease.

Heterozygous mutations in the ACAN gene have been reported in individuals with short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans. We report a family with a phenotypic constellation carrying a novel mutation in the ACAN gene. The proband was a 7-year-old Japanese girl with short stature. Her mother and maternal grandmother also had short stature and intervertebral disc disease. We analyzed the ACAN gene in the family and identified a novel heterozygous mutation: c.4634delT, Leu1545Profs*11.

Relapsing 6q24-related transient neonatal diabetes mellitus with insulin resistance: A case report.

The overexpression of imprinted genes on chromosome 6q24 causes 6q24-related transient neonatal diabetes mellitus (6q24-TNDM). Most cases of 6q24-TNDM show transient diabetes mellitus (DM) during the neonatal period, followed by relapse after puberty. These two courses of DM are both characterized by insulin insufficiency. However, there has been no previously reported case of 6q24-TNDM with insulin resistance at relapse. We report the case of a 10-yr-old Japanese girl with relapsing 6q24-TNDM. In the neonatal period, she had hyperglycemia and was treated with insulin injection until 2 mo of age. After several years of remission of DM, her HbA1c level increased to 7.4% at 10 yr of age. Homeostasis model assessment of insulin resistance (HOMA-IR) score was high at 6.2. After starting metformin therapy, her glycemic control improved along with normalization of HOMA-IR score. Using microsatellite marker analysis on the 6q24 region and array comparative genome hybridization, we diagnosed her with 6q24-TNDM due to paternally inherited duplication of 6q24. These data indicate that patients with 6q24-TNDM can develop relapsing DM with insulin resistance.

A neonatal case of HDR syndrome and a vascular ring with a novel GATA3 mutation.

HDR syndrome (OMIM #146255) is caused by haploinsufficiency of the GATA3 gene. A vascular ring has not been reported in patients with GATA3-associated HDR syndrome. We report a neonatal case of HDR syndrome and a vascular ring that were possibly due to a novel frameshift mutation in the GATA3 gene.

A Novel Case of Somatic KCNJ5 Mutation in Pediatric-Onset Aldosterone-Producing Adenoma.

Aldosterone-producing adenoma (APA), a subtype of primary aldosteronism, is a common cause of secondary hypertension in adults. Somatic KCNJ5 mutations have been identified in about 12%-80% of adult-onset APA. In contrast, there has been no previous reported case of pediatric-onset APA in whom a somatic KCNJ5 mutation was confirmed. We report an 11-year-old Japanese girl who had experienced recurrent headaches and nausea for more than 2 years before hypertension was observed (blood pressure, 150/82 mm Hg). Plasma renin activity was <0.1 ng/mL per hour even after a captopril-challenge or upright furosemide-loading test. Plasma aldosterone concentrations (PACs) before and after saline-infusion test were 28.0 and 40.6 ng/dL, respectively. Plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels were 16.5 pg/mL and 16.7 µg/dL, respectively. The patient was diagnosed with APA in the left adrenal gland on the basis of selective adrenal venous sampling after ACTH stimulation (PAC in the left adrenal vein, 3630 ng/dL) and histopathologic findings of the tumor obtained by laparoscopic left adrenalectomy. Sanger sequencing of KCNJ5 using genomic DNA from peripheral lymphocytes and laser-captured microdissected APA tissues demonstrated the presence of a somatic KCNJ5 mutation p.L168R, previously reported only in adult-onset APA. Immunohistochemistry detected strong immunoreactivity for CYP11B2, but not for CYP11B1 in the APA, consistent with the endocrinologic findings in this patient. Somatic KCNJ5 mutations are also identified in pediatric-onset APA. Further cases are needed to elucidate functional characteristics of pediatric-onset APA with a somatic KCNJ5 mutation.