Brachydactyly type E is characterized by variable shortening of the metacarpals and/or metatarsals [Temtamy and Aglan, 2008;Mundlos, 2009]. PTHLH is one of the genes associated with this type of brachydactyly, and since its involvement in this trait was discovered [Klopocki et al., 2010;Maass et al., 2010], nine intragenic point mutations [Klopocki et al., 2010;Wang et al., 2015;Jamsheer et al., 2016;Thomas-Teinturier et al., 2016] have been described as causative of BDE with short stature, PTHLH type (OMIM#613382). Most of the reported patients have had short stature or stature within the lower range of normality and some of them present normal stature at diagnosis [Klopocki et al., 2010;Jamsheer et al., 2016;Thomas-Teinturier et al., 2016], though final height is usually below the target height [Thomas-Teinturier et al., 2016].There are no data in the bibliography about the recurrence of these nine mutations in other non-related families, and hence, it is difficult to make genotype-phenotype correlations. Given this state-of-affairs, we considered it important to report our patient with BDE, who harbors the p.R56 Ã mutation first described recently [Jamsheer et al., 2016].The patient was Caucasian girl who was referred to the endocrinologist at 9 years and 10 months old for pubarche and apocrine sweat from 7 years of age. She was born at 39 weeks of gestation, with low weight for gestational age (weight 1950 g, À3.32 SD; length 47 cm, À1.47 SD). After the neonatal period, she had been a healthy girl with a normal growth rate. Her parents were healthy and non-consanguineous. The mother's height was 169 cm and the age of her menarche was 13 years old. The father was 172 cm tall, and hence, the girl's target height was 164 cm. Parents did not present brachydactyly.At the time of the first visit, she had a normal height (137.9 cm, 0 SD) with mild overweight (weight 44.3 kg, 1.2 SD; body mass index 23.3 kg/m 2 , 1.7 SD). The physical examination revealed a P2 B1 Tanner stage, round face, long philtrum, short neck, descended and widely separated nipples, and small hands and feet, with shortening of all the metacarpals and the distal phalanges of the first and third fingers (Fig. 1A) and shortening of third, fourth, and fifth metatarsals (Fig. 1B). A hand roentgenogram showed premature fusion of the epiphyses in the shortened bones and cone-shaped epiphyses (Fig. 1A) with a bone age of approximately 12 years when she was 9 years and 8 months old (Fig. 1C). Blood tests and an abdominal ultrasound examination were performed, results ruling out congenital adrenal hyperplasia and adrenal tumors.At the age of 10 years and 8 months, she had a bone age of 13.5 years (Fig. 1C), and her growth rate did not show a clear pubertal growth spurt. She had the menarche when she was 11 years old. In the most recent visit, when she was 12 years old, she was 148.7 cm tall (À0.4 SD) and her growth rate in the previous year had been 4.2 cm/year; this suggests an early completion of growth resulting in short stature for her target height, ...
We report the clinical and genetic findings in a 15‐year‐old Spanish boy presenting prenatal and postnatal growth retardation, reduced subcutaneous adipose tissue, premature skin wrinkling, sparse hair, short distal phalanges with small nails, umbilical hernia, wide anterior fontanel, and normal cognitive and motor development. Exome sequencing uncovered a heterozygous mutation in SLC25A24 (NM_013386: c.650G>A: p.R217H) that encodes for the calcium‐binding mitochondrial carrier protein SCaMC‐1. This gain‐of‐function variant has been previously associated with Fontaine syndrome and Gorlin‐Chaudhry‐Moss syndrome, two entities that show overlapping features, and have been recently subsumed under the name Fontaine progeroid syndrome (FPS; MIM: 612289) in OMIM. Here, we describe the first male patient with genetically confirmed FPS who survives at least until adolescence.
Context Heterozygous variants in the Indian hedgehog gene (IHH) have been reported to cause brachydactyly type A1 and mild hand and feet skeletal anomalies with short stature. Genetic screening in individuals with short stature and mild skeletal anomalies has been increasing over recent years, allowing us to broaden the clinical spectrum of skeletal dysplasias. Objective The objective of this article is to describe the genotype and phenotype of 16 probands with heterozygous variants in IHH. Patients and Methods Targeted next-generation sequencing or Sanger sequencing was performed in patients with short stature and/or brachydactyly for which the genetic cause was unknown. Results Fifteen different heterozygous IHH variants were detected, one of which is the first reported complete deletion of IHH. None of the patients showed the classical phenotype of brachydactyly type A1. The most frequently observed clinical characteristics were mild to moderate short stature as well as shortening of the middle phalanx on the fifth finger. The identified IHH variants were demonstrated to cosegregate with the short stature and/or brachydactyly in the 13 probands whose family members were available. However, clinical heterogeneity was observed: Two short-statured probands showed no hand radiological anomalies, whereas another 5 were of normal height but had brachydactyly. Conclusions Short stature and/or mild skeletal hand defects can be caused by IHH variants. Defects in this gene should be considered in individuals with these findings, especially when there is an autosomal dominant pattern of inheritance. Although no genotype-phenotype correlation was observed, cosegregation studies should be performed and where possible functional characterization before concluding that a variant is causative.
Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO‐ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as “uncertain significant variants”, and therefore, carry out cascade family screening.
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