PTHLH gene variant in an Indian boy with brachydactyly type E: A case report and literature review

Abstract.

Concerns regarding linear growth and dysmorphic features are common in several genetic syndromes. Among these, PTHLH-related brachydactyly type E (BDE), which is inherited in an autosomal dominant manner, is a rare but distinct genetic disorder. This condition is caused by heterozygous variants in the PTHLH gene, which encodes a parathyroid hormone-related protein, a key regulator of endochondral bone development. To date, very few cases of this condition have been reported. Here, we describe a case of a PTHLH gene variant (heterozygous for c.54C>G p.Tyr18Ter) in an Indian boy who presented with linear growth problems, BDE, and subtle dysmorphism. This case underscores the importance of genetic evaluation to clarify ambiguous clinical presentations and guide appropriate management strategies. This detailed phenotypic characterization of the early truncating PTHLH variant p.Tyr18Ter expands the clinical spectrum associated with PTHLH haploinsufficiency.

Highlights

● First reported case of PTHLH gene variant in an Indian boy with BDE

● PTHLH gene variant (heterozygous for c.54C>G p.Tyr18Ter) is associated with a characteristic skeletal phenotype

Introduction

Variations in linear growth accompanied by dysmorphic features are a hallmark of numerous genetic syndromes, often reflecting underlying disruptions in skeletal development. The etiology of growth failure under these conditions is diverse, encompassing hormonal, structural, and genetic mechanisms. Recent genomic studies have identified hundreds of variants across more than 180 loci that influence human height through pathways critical for skeletal growth and development (1). Among these, PTHLH-related brachydactyly type E (BDE) is a rare but distinct genetic disorder characterized by disproportionately short hands and feet due to the abnormal development of the metacarpals, metatarsals, and/or phalanges, most notably affecting the fourth and fifth digits (2). This condition is inherited in an autosomal dominant pattern and results from heterozygous variants of the PTHLH gene, which encodes the parathyroid hormone (PTH)-related protein (PTHrP), a key regulator of endochondral bone development (2).

To date, only a limited number of PTHLH-related BDE cases have been documented in the literature, making each new report valuable for expanding the phenotypic and genotypic spectrum of this disorder (2,3,4,5,6,7,8,9,10). Here, we present the case of a 13.5-yr-old Indian boy who presented with concerns regarding linear growth, subtle facial dysmorphism, and radiological features consistent with BDE, in whom a known pathogenic variant of PTHLH was identified through whole-exome sequencing (WES). This case underscores the importance of genetic evaluation to clarify ambiguous clinical presentations and guide appropriate management strategies. Genetic diagnosis not only facilitates accurate classification of skeletal dysplasia but also informs prognosis, enables targeted counselling, and supports individualized care planning.

Case Presentation

A 13.5-yr-old boy presented to the pediatric endocrinology outpatient clinic with concerns regarding linear growth. He was the first son of a non-consanguineous couple. The patient was born at term after normal pregnancy, weighing 2.1 kg. There were no concerns during the perinatal period except that he was small for gestational age (SGA); however, no specific explanation for SGA was found. His developmental milestones were considered appropriate for age. He was intellectually normal and had good scholastic performance. There was no family history of short stature or constitutional delay in growth and puberty (CDGP).

Upon examination, he had mild facial dysmorphism, including a depressed nasal bridge, dolichocephaly, tall forehead, mild hypertelorism, and a round face with mid-face hypoplasia (Fig. 1). The results of the dental examination were normal. Skeletal findings included shortening of the 3^rd to 5^th metacarpals with cone-shaped epiphyses, shortening of the metatarsals from the 2^nd to 5^th digits (Figs. 2A and B), clinodactyly of the 5^th finger, short long bones, and short limbs (Figs. 3A–C). He also presented with broad feet, short toes, and hallux valgus (Fig. 3C). His nails and joint mobility were normal, and intelligence was maintained, with no significant systemic involvement. There were no subcutaneous ossifications, café-au-lait spots, or history of fractures. At 13.5 yr, his height was 146.5 cm (10^th percentile or −1.32 SD); weight, 49.2 kg (50^th percentile or 0.33 SD); and mid-parental height (MPH), 168 cm. Although not short, his height corresponded to the lower half of the target height range. His upper body segment (76 cm) to lower body segment (68 cm) ratio was 1.1 and arm span was 143 cm, with a slightly reduced arm span to height ratio of 0.97. At the time of presentation, he was prepubertal (Tanner stage 1) with no axillary (A1) or pubic hair (P1) and testes measuring 3 mL bilaterally. His skeletal age was delayed by one year at presentation. During his latest visit at the age of 14 yr, there were some clinical signs of the onset of puberty, with the testes measuring 4 mL bilaterally and recent onset of pubic hair development. Laboratory parameters, including complete blood count, thyroid profile, renal profile, liver function test, random blood glucose, and insulin-like growth factor 1 (IGF1), were normal. His PTH (45 pg/mL), calcium (9.2 mg/dL), and phosphorus (4.5 mg/dL) levels were normal. His vitamin D level was low; therefore, supplementation was provided. Basal gonadotropin and testosterone levels were in the prepubertal range at the time of presentation.

Fig. 1.

Facial features: note the depressed nasal bridge, tall forehead, mild hypertelorism.

Fig. 2.

A: Hand radiographs: shortening of the 3^rd to 5^th metacarpals, with cone shaped epiphyses. B: Foot radiographs: short metatarsals and hallux valgus.

Fig. 3.

A: Hands: note the short fingers and clinodactyly of the 5^th finger. B: Fist: note the retraction of the knuckles (3^rd, 4^th, 5^th) because of short metacarpals. C: Feet: note broad feet with short toes and hallux valgus.

The provisional diagnoses were SGA, CDGP, or possible skeletal dysplasia. He was referred to a clinical geneticist for further evaluation of short limbs and facial dysmorphism.

Genetic work-up

Considering the patient’s short limbs, facial dysmorphism, and radiological evidence of shortened metacarpals and metatarsals suggestive of brachydactyly, a syndromic form of acromelic dysplasia was suspected. The differential diagnoses included BDE, Albright hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP), hypertension-brachydactyly syndrome, and HOXD13-related skeletal dysplasia.

Given the phenotypic complexity of this case and the absence of a definitive clinical diagnosis, next-generation sequencing-based (NGS)-based WES was performed. Genetic analysis revealed a heterozygous, likely pathogenic, nonsense variant, c.54C>G (p.Tyr18Ter), in the PTHLH gene. This variant has been previously reported to be associated with PTHLH-related BDE.

Pseudohypoparathyroidism was excluded based on the absence of biochemical PTH resistance and normal serum calcium and phosphate levels; therefore, GNAS methylation analysis was not performed. Both parents were phenotypically normal and exhibited no evidence of growth impairment or brachydactyly. Genetic counselling was provided, and parental PTHLH genetic testing was recommended; however, molecular testing in the parents has not yet been performed.

Discussion

We describe a case of PTHLH-related BDE in a boy presenting with concerns regarding linear growth and dysmorphism. Brachydactyly refers to a spectrum of limb malformations characterized by the shortening of hands, feet, or both (11, 12). BDE is rare and can be an isolated finding or part of one or more genetic syndromes (13, 14). Maass et al. were the first to implicate the PTHLH gene in BDE with growth impairment, after the identification of a translocation, t(8; 12) (q13; p11.2), in a family with an autosomal dominant pattern of inheritance (2).

PTHrP plays a key role in endochondral bone development and skeletal health. It is encoded by PTHLH, which binds to the PTH/PTHrP receptor (PTH1R). It is expressed in the periarticular growth plate and functions through PTH1R to maintain chondrocytes in a state of growth, while delaying hypertrophic differentiation (15). This process ensures that long bones grow properly. This function is carefully regulated by a feedback loop that includes Indian hedgehog (IHH) signaling. Taken together, these results suggested that IHH and PTHrP control the speed of growth plate maturation and endochondral ossification. Disruptions in this system, whether from variants that decrease or increase function in PTHLH or PTH1R, can lead to early chondrocyte hypertrophy and skeletal dysplasia. This demonstrates the importance of balanced PTHrP signaling in normal bone development (16, 17). Variants in PTH1R, which encodes the PTH/PTHrP receptor, result in a broad phenotypic spectrum ranging from lethal skeletal dysplasias, such as Blomstrand chondrodysplasia and Eiken syndrome, to milder conditions, including Jansen’s metaphyseal chondrodysplasia and primary failure of tooth eruption. These disorders differ mechanistically from PTHLH-related BDE, in which reduced ligand availability predominantly leads to digital shortening with mild or no growth impairment. Although PTHLH variants primarily result in ligand haploinsufficiency, PTH1R variants may exert loss- or gain-of-function effects at the receptor level, accounting for wider clinical variability. A comparative summary of PTHLH- and PTH1R-related disorders is presented in Table 1.

Table 1. Comparison of PTHLH- and PTH1R-related disorders.

The identified PTHLH variant, c.54C>G (p.Tyr18Ter), introduces a premature termination codon in exon 4 of 6 and is predicted to result in loss of function through nonsense-mediated mRNA decay and/or a truncated protein product. Because PTHLH haploinsufficiency is an established mechanism for BDE, the variant was classified as likely pathogenic based on the American College of Medical Genetics and Genomics criteria (including PVS1 and PM2). This variant was submitted to ClinVar as likely pathogenic for brachydactyly type E2; however, detailed phenotypic information is unavailable in the public domain. In contrast, our patient showed a well-characterized BDE phenotype with generalized shortening of the metacarpals/metatarsals and short long bones, mild craniofacial dysmorphism, and normal biochemical parameters and neurodevelopment, supporting a relatively mild skeletal phenotype associated with an early truncating PTHLH variant (10, 11).

BDE may be isolated or part of skeletal dysplasias. BDE phenotypes vary significantly among published reports (2,3,4,5,6,7,8,9,10). BDE exhibits variable expression even within families, ranging from isolated shortening of select metacarpals to a more generalized involvement of bones in the hands and feet. There are reports of PTHLH-related BDE in which affected individuals exhibit short stature or impaired growth patterns. Klopocki et al. described 13 affected individuals from five families, of whom 10 had short stature (4). In the same study, premature closure of epiphyses was observed in some affected individuals, which could explain their short stature (4). Our patient, although not short, was in the lower half of the target height range. Since he was born SGA, there was a possibility of reduced total height gain and faster bone maturation during puberty, leading to reduced final height. In our patient, the skeletal age was delayed by approximately one year. Jamsheer et al. also reported delayed skeletal age and craniofacial dysmorphism (8), similar to the findings of our case. In the present case, the degree of skeletal maturation delay (approximately one year) was disproportionate to the degree of pubertal delay. Although delayed pubertal onset typically contributes to delayed bone maturation, PTHLH haploinsufficiency has been associated with premature hypertrophic differentiation of growth plate chondrocytes and disturbed bone maturation, which may accelerate local skeletal maturation. The interplay between these opposing biological mechanisms may explain the relatively modest delay in bone aging observed in our patient (17).

Klopocki et al. described learning difficulties in one family in their cohort (4). Our patient did not experience any apparent learning difficulties. Scheffer-Rath et al. also described learning difficulty and speech delay in a family in which three siblings and the mother had a heterozygous variant c.25T>C, p.Trp9Arg in exon 2 of the PTHLH gene (5). Oligodontia and dental abnormalities have been described in some families (4, 5). Flottmann et al. described BDE with osteochondroplasia and rhizomelia in a family spanning three generations (17). In addition to these clinical features, pectus carinatum with BDE has been described in a Chinese family with nine affected individuals with a 3.06-Mb deletion of 12p12.1–12p11.22 (9).

Our patient was born SGA. Although SGA is not a defining feature of PTHLH-related BDE, PTHrP plays a critical role in fetal endochondral ossification and placental calcium transport, both of which are essential for normal linear growth during intrauterine life (16). Previous reports of individuals with pathogenic PTHLH variants have demonstrated variable growth phenotypes, including impaired prenatal and postnatal growth, suggesting that reduced PTHrP signaling during fetal development may contribute to diminished skeletal growth in utero (5). This observation supports the possible contributory role of PTHLH dysfunction in the SGA phenotype and further expands the clinical spectrum of PTHLH-related disorders. From the literature, it is clear that PTHLH-related BDE can present significantly variable phenotypes.

Multiple genetic defects have been identified in patients with BDE with PTHLH gene variants. Our patient was heterozygous for c.54C>G p.Tyr18Ter in PTHLH. It is a variant associated with BDE and has variable growth patterns (10). Till now, two cases of balanced translocation, including t(8; 12) (q13; p11.2) and t(4; 12) (q13.2–13.3; p11.2), causing the downregulation of the PTHLH gene by disrupting the cis-regulatory and trans-regulatory landscape, have been reported by Maass et al. (2, 3). Later, several authors reported microdeletions and duplications at several loci. Klopocki et al. described a 907-kb genomic microdeletion on chromosome 12p that affected six genes (4). Huang et al. identified a 3.06-Mb interstitial deletion at 12p11.22–12.1 (9). Flottmann et al. described a 70-kb duplication on chromosome 12p11.22 in a family of three generations with osteochondroplasia with a combined brachydactyly type E/A1 phenotype with disturbed bone maturation and rhizomelia (17). Jamsheer et al. described two novel truncating PTHLH variants (heterozygous frameshift variant c.258delC(p.N87Tfs*18) and heterozygous c.166C>T(p.R56*) that resulted in variable combinations of BDE and other symptoms.

Conclusion

In conclusion, we describe a case of BDE and dysmorphism associated with a likely heterozygous pathogenic variant, c.54C>G (p.Tyr18Ter), in the PTHLH gene. Identifying the genetic etiology in cases of subtle dysmorphisms in children helps with precise diagnosis, appropriate treatment planning, genetic counseling, and family screening.

Conflict of interests

The authors have no competing interests to declare.