The p.R56* mutation in PTHLH causes variable brachydactyly type E

Abstract

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, ...

What to consider when pseudohypoparathyroidism is ruled out: iPPSD and differential diagnosis

“…The BDE PTHLH type was suspected in two patients with BDE and advanced bone maturation for their chronological age. Indeed, two different novel mutations (c.101+ 3delAAGT, in PHP11 [ 34 ] and c.166C>T/p.Arg56*, in PHP12 [ 35 ]) were identified in the PTHLH gene in these patients. The characteristics of these mutations (frameshift and nonsense, respectively) suggested that they were causative of the pathology.…”

A Heterozygous Splice-Site Mutation in PTHLH Causes Autosomal Dominant Shortening of Metacarpals and Metatarsals

“…(2)(3)(4)(5)10,11,(35)(36)(37) Likewise, PTHrP haploinsufficiency can lead to variable shortening of one or multiple metacarpals and metatarsals, but also to short stature implying that chondrocytes in multiple growth plates undergo accelerated differentiation. (25)(26)(27)(28)(29)(30)(31) It is therefore likely that haploinsufficiency of PTHrP-dependent signaling at the PTHR1 reduces intracellular cAMP levels in growth plate chondrocytes to a similar extent as heterozygous PDE4D, PDE3A, and PRKAR1A mutations, or the reduction of Gsa protein levels through genetic or epigenetic mechanisms.…”

“…Similar skeletal findings are encountered in patients with mutations in PDE3A , SHOX , or HDAC4 that are associated with different additional abnormalities. Likewise, mutations in PTHLH , the gene encoding PTHrP, lead to shortening of bones in hands and feet, and are usually associated with short stature, but no other clinically apparent defects . Importantly, genetic mutations in GNAS and PRKAR1A (and occasionally in PDE4D ) are associated with readily detectable laboratory abnormalities.…”

“…Likewise, mutations in PTHLH, the gene encoding PTHrP, lead to shortening of bones in hands and feet, and are usually associated with short stature, but no other clinically apparent defects. (25)(26)(27)(28)(29)(30)(31) Importantly, genetic mutations in GNAS and PRKAR1A (and occasionally in PDE4D) are associated with readily detectable laboratory abnormalities. Consequently, the absence or presence of hormonal resistance can help reduce the list of plausible candidate genes that are responsible for shortening of one or several metacarpals.…”

Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause

“…1; blue text). These molecular defects include translocations [34], microdeletions [35,36], and heterozygous missense, nonstop, or nonsense mutations [35][36][37][38][39].…”