Eiken syndrome presenting as pseudohypoparathyroidism due to PTH1R gene pathogenic variant

Abstract

Pseudohypoparathyroidism (PHP) is a rare disorder characterized by classic hypocalcemia despite normal or elevated parathyroid hormone (PTH). Pseudohypoparathyroidism is marked by tissue resistance to circulating PTH and is associated with the typical Albright hereditary osteodystrophy (AHO) phenotype, including developmental delay, obesity, short stature, round face, brachydactyly, and ectopic ossifications. Pseudohypoparathyroidism is classified into multiple types based on the extent of clinical features and hormonal resistance beyond the parathyroid glands. We present a 15-year-old boy with recurrent seizures, developmental delay, deafness, poor dentition, and skeletal dysplasia. He did not have the typical AHO phenotype, and investigations revealed severe hypocalcemia, hyperphosphatemia, and elevated PTH, supporting a diagnosis of PHP. Imaging showed bilateral basal ganglia calcification, brachydactyly, clinodactyly, ischiopubic hypoplasia, and skeletal changes beyond those typically observed in patients with typical PHP. Whole-exome sequencing revealed a homozygous missense variant in exon 9 of the PTH1 receptor (PTH1R) gene, suggestive of Eiken syndrome (ES). This variant has not been described in the handful of published cases of ES, and we highlight the rare PTH1R pathogenic variant that leads to PHP and skeletal dysplasia.

Introduction

Pseudohypoparathyroidism (PHP) is a rare, heterogenous disorder characterized by target-organ resistance to circulating parathyroid hormone (PTH). Pseudohypoparathyroidism is classified as type 1 or type 2, with blunted or normal cyclic adenosine monophosphate (cAMP) response, respectively [1]. Type 1 PHP is further subdivided into 1a, 1b, and 1c, based on unresponsiveness to PTH in target tissues, including the parathyroid gland, kidney, and others [2]. Albright hereditary osteodystrophy is the characteristic phenotype of PHP consisting of obesity, developmental delay, and skeletal malformations [3]. All patients with PHP have hypocalcemia, hyperphosphatemia, and paradoxically normal or elevated PTH. The typical brain imaging finding in PHP is bilateral basal ganglia calcification (BGC), resulting from activation of osteogenic molecules in the basal ganglia due to hyperphosphatemia [4]. Fahr syndrome is a rare neurologic disorder characterized by extrapyramidal abnormalities and BGC, which may be misdiagnosed as PHP due to overlapping clinical features [5].

Eiken syndrome (ES) is an exceptionally rare autosomal recessive skeletal dysplasia described in fewer than 10 cases worldwide, caused by biallelic variants in the PTH1 receptor (PTH1R) gene [6]. It is characterized by delayed ossification, epiphyseal dysplasia, and bone remodeling abnormalities [7]. Eiken syndrome with PTH1R variants can be broadly divided into those presenting with skeletal dysplasia and those with PTH resistance [8]. Patients with isolated skeletal dysplasia have mutations in the extracellular C-terminal tail or the N-terminal ligand-binding domain that affect the cAMP response to PTH-related protein (PTHrP) but not to PTH. Patients with skeletal dysplasia and PTH resistance have mutations in transmembrane domain 2 that alter the cAMP response to both PTHrP and PTH [8]. We report a 15-year-old boy who was initially diagnosed with Fahr syndrome at age 2 years due to seizures and BGC. Subsequent evaluation showed typical biochemical features of PHP. Whole-exome sequencing (WES) revealed a previously undescribed variant in the PTH1R gene, leading to a diagnosis of ES.

Case presentation

A 15-year-3-month-old boy was referred with recurrent seizures and hypocalcemia. He was the firstborn of a nonconsanguineous couple, born at full term via normal vaginal delivery with a birth weight of 2.5 kg, following an uneventful antenatal and postnatal period. He met developmental milestones normally and had average scholastic performance. The mother reported that seizures began at 10 months of age, and he was started on antiepileptic therapy. Brain imaging performed in childhood demonstrated BGC, and antiepileptic agents were stepped up due to recurrent seizures. Poor dentition was noted since childhood, with delayed eruption and malformed teeth. He was diagnosed with hypothyroidism at 13 years of age and is taking levothyroxine 25 mcg daily; the previous medical record did not have a calcium level. The mother noticed that the boy was growing more slowly than peers but did not seek consultation specifically for it and attributed it to the seizure disorder. In the year preceding presentation at our hospital, the boy had experienced increased seizure frequency, giddiness, and progressive hearing loss. A report from a year earlier showed serum calcium 7.1 mg/dL (International system of units [SI]: 1.77 mmol/L) (reference range: 8.5-10.5 mg/dL; 2.12-2.62 mmol/L), phosphorus 9.8 mg/dL (SI: 3.16 mmol/L) (reference range: 2.5-4.9 mg/dL; 0.81-1.58 mmol/L), alkaline phosphatase 295 IU/L (SI: 4.9 µkat/L) (reference range: 175-773 U/L; 2.9-12.9 µkat/L), 25-hydroxy vitamin D (25 OHD) 11.7 ng/mL (SI: 29.2 nmol/L) (reference range: >30 ng/mL; >75 nmol/L), and intact PTH 236.5 pg/mL (SI: 25.1 pmol/L) (reference range: 15-65 pg/mL; 1.6-6.9 pmol/L). The patient has 2 siblings without similar complaints or skeletal abnormalities.

Diagnostic assessment

His examination revealed a height of 150 cm (below the third centile; −2.1 standard deviation score [SDS]), a weight of 36 kg (third centile; −2 SDS), and a body mass index of 16 kg/m², with normal vital signs. He has a wide forehead, a flat nasal bridge, a small philtrum, an everted lower lip, severe dental deformities with delayed eruption and premature loss of teeth (Fig. 1A), bilateral clinodactyly (Fig. 1B), an elongated thumb and great toe, forearm deformity, and a bony swelling over the dorsal aspect of the left foot (Fig. 1C). Pubertal assessment showed Tanner stage A1P3, with bilateral testicular volume of 6 mL and stretched penile length of 6 cm. Trousseau sign was positive, and Chvostek sign was negative. His fundus and other systemic examinations were normal.

Figure 1.

Clinical photographs showing typical facial features of ES (A), clinodactyly (B), and bony deformity of left foot (C).

Radiographs demonstrated delayed skeletal maturation, with bone age per the Greulich-Pyle atlas corresponding to 12 years. Hand and foot radiographs showed brachydactyly with shortened, dysplastic middle phalanges resembling a type A1 brachydactyly pattern, bilateral clinodactyly, delayed carpal maturation, and diffuse phalangeal deformities (Fig. 2A). A foot radiograph revealed broad, dysplastic epiphyses, and deformities of the short tubular bones (Fig. 2B). A pelvic radiograph demonstrated relative ischiopubic hypoplasia, while the proximal femora showed broad femoral necks with reduced tapering, suggestive of femoral epiphyseal dysplasia (Fig. 2C). Orthopantomogram revealed poor mineralization, multiple unerupted teeth, and hypercementosis (Fig. 3A), and an axial computed tomography (CT) scan of the brain showed BGC (Fig. 3B). Audiological evaluation demonstrated moderate conductive hearing loss in the right ear and profound mixed hearing loss in the left ear.

Figure 2.

Hand radiograph showing delayed bone age and type A1 brachydactyly (A), foot radiograph showing bony deformity and short tubular metatarsals (B), and pelvic radiograph showing ischiopubic hypoplasia and deformed femoral neck (C).

Figure 3.

Orthopantomogram showing unerupted teeth (A) and axial CT scan of the brain showing bilateral BGC (B).

Our differential diagnosis was either PHP or PTH1R-related skeletal dysplasia, and his investigations revealed serum calcium 6.4 mg/dL (SI: 1.59 mmol/L), phosphorus 9.6 mg/dL (SI: 3.1 mmol/L), alkaline phosphatase 202 IU/L (SI: 3.4 µkat/L), 25-OHD 12.9 ng/mL (SI: 32.2 nmol/L), and PTH 209 pg/mL (SI: 22.2 pmol/L), confirming a pattern consistent with PHP. Other hormonal parameters, including thyrotropin, insulin-like growth factor 1, luteinizing hormone, and testosterone, were normal. The rest of the biochemical panel, including glucose, creatinine, and magnesium, was also normal.

Whole-exome sequencing identified a homozygous missense variant in exon 9 of the PTH1R gene (chr3:g.46898723G>A) that results in substitution of threonine for alanine at codon 234 (p.Ala234Thr; ENST00000449590.6), suggestive of ES. The variant has not been previously reported and is classified as a variant of uncertain significance (VUS). Although the identified variant is classified as VUS, we consider that it has a pathogenic role, as the substitution lies in the transmembrane domain 2 of PTH1R, the same functional domain in which the recently described pathogenic variants p.Ile237Asn and p.Asp241Glu have been shown to cause ES with PTH resistance [8, 9]. Exome sequencing also identified a few other variants in our patient, as shown in Table 1, that correlate with the clinical presentation of developmental delay and epilepsy (ACTL6B) and deafness (MYO7A).

Table 1.

Details of pathogenic variants identified in the patient

Gene	Variant details	Zygosity	Online Mendelian Inheritance in Man (OMIM) disease
PTH1R (+)	c.700G>A p.Ala234Thr ENST00000449590.6 NM_000316.3	Homozygous	(OMIM#600002)
ACTL6B (−)	c.1120C>T p.Arg374Ter ENST00000160382.10 NM_016188.5	Heterozygous	(OMIM#618468)
MYO7A (+)	c.5594C>T p.Pro1865Leu ENST00000409709.9 NM_000260.4	Heterozygous	(OMIM#601317) (OMIM#600060)

Treatment

The patient was initially treated with an intravenous calcium infusion for 24 hour and sevelamer 800 mg 3 times daily to correct severe hypocalcemia and hyperphosphatemia, respectively. We administered cholecalciferol 60 000 IU orally weekly, along with a daily 2000-IU supplement, to correct vitamin D deficiency. We stopped sevelamer after 7 days and started the patient on oral calcitriol 0.25 µg twice daily. His antiepileptic medications were adjusted to include levetiracetam and clonazepam. We transitioned from intravenous calcium to oral calcium gluconate, 500 mg every 4 hour. His levothyroxine dose of 25 µg was continued in view of normal thyrotropin. After correcting hyperphosphatemia and vitamin D deficiency, we repeated the biochemical parameters. Table 2 shows serial biochemical parameters, and biochemical evidence of PTH resistance persisted even after vitamin D adequacy.

Table 2.

Serial changes of the biochemical parameters in the patient

Variable	Reference range	Previous results (March 2025)	First visita (March 2026)	After correction of vitamin D deficiency (VDD) (May 2026)	Last review (June 2026)
Calcium	8.5 to 10.5 mg/dL (SI: 2.12-2.62 mmol/L)	7.1 mg/dL (SI: 1.77 mmol/L)	6.4 mg/dL (SI: 1.59 mmol/L)	7.6 mg/dL (SI: 1.89 mmol/L)	8 mg/dL (SI: 2 mmol/L)
Phosphorus	2.5 to 4.9 mg/dL (SI: 0.81-1.58 mmol/L)	9.8 mg/dL (SI: 3.16 mmol/L)	9.6 mg/dL (SI: 3.1 mmol/L)	6.4 mg/dL (SI: 2.1 mmol/L)	6.2 mg/dL (SI: 2 mmol/L)
Alkaline phosphatase	175 to 773 IU/L (SI: 2.9-12.9 µkat/L)	295 IU/L (SI: 4.9 µkat/L)	202 IU/L (SI: 3.4 µkat/L)	182 IU/L (SI: 3 µkat/L)	156 IU/L (SI: 2.6 µkat/L)
25-Hydroxy vitamin D	>30 ng/mL (SI: >75 nmol/L)	11.7 ng/mL (SI: 29.2 nmol/L)	12.9 ng/mL (SI: 32.2 nmol/L)	42 ng/mL (SI: 104.8 nmol/L)	Not done
PTH (intact)	15 to 65 pg/mL (SI: 1.6-6.9 pmol/L)	236.5 pg/mL (SI: 25.1 pmol/L)	209 pg/mL (SI: 22.2 pmol/L)	162 pg/mL (SI: 17.2 pmol/L)	Not done

Values in parentheses are International System of Units.

Abbreviations: PTH, parathyroid hormone; VDD, vitamin D deficiency.

^aSevelamer was given for 7 days at the first visit in March 2026.

Outcome and follow-up

The patient is currently treated with 3000 mg of oral calcium gluconate daily, administered in 4-hour intervals; cholecalciferol of 2000 IU; calcitriol 0.5 µg daily in a double dose; and levothyroxine 25 µg daily. The neurologist advised continuing levetiracetam alone and discontinued clonazepam. A dental consultation was obtained for poor dentition, and the patient is undergoing workup for dental implants at a later date. The patient remains seizure-free, and his calcium and phosphorus were 8 mg/dL (SI: 2 mmol/L) and 6.2 mg/dL (SI: 2 mmol/L), respectively, at the last follow-up.

Discussion

We present a young boy with recurrent seizures due to severe hypocalcemia and significant skeletal abnormalities. His diagnosis was initially Fahr disease and was later changed to PHP based on the typical biochemical profile. However, atypical skeletal features in a nonobese patient prompted us to consider an alternative diagnosis, and WES provided the final diagnosis of ES. Our case highlights the diagnostic complexity of differentiating ES with PTH resistance from genetically heterogenous causes of PTH resistance [10]. Delayed bone age and type A1 brachydactyly (compared with advanced bone age and type E brachydactyly in PHP) led us to suspect ES with PTH resistance and to proceed directly to WES, without sequential molecular testing as suggested by the conventional approach [11].

Eiken syndrome has been described in 9 cases worldwide to date, and to the best of our knowledge, this is the 10th case reported in the English-language literature. Hypocalcemia and PTH resistance were not described in the initial reports but were reported in a recent report [8]. Our patient had increased seizure frequency in infancy and at puberty, which may reflect increased calcium requirements during periods of rapid growth. Although we do not have documented hypocalcemia prior to 14 years of age, we consider it resulting from ES with PTH resistance, which reports hypocalcemic seizures as early as the first week of life and at 10 months [8, 9].

Calder et al [8] reported the eighth and ninth cases of ES and summarized all published reports of ES, including the functional analysis of PTH1R variants. Parathyroid hormone receptor type 1 is activated by 2 ligands, PTH, which mediates calcium homeostasis, and PTHrP, which mediates chondrocyte development. PTH1R pathogenic variants lead to Bloom syndrome, Jansen metaphyseal chondrodysplasia, and ES [12]. Functional characterization is essential, as patients with ES have shown characteristics of both gain-of-function (delayed mineralization) and loss-of-function (failure of primary tooth eruption) features [13]. Moreover, initial reports did not show calcium metabolism abnormalities, whereas later reports have shown a typical PHP profile. Short stature was seen in only 4 of 9 cases, and our patient also had short stature.

Eiken syndrome was initially described in a Turkish family and subsequently in individuals of Indian and East African ancestry [8, 13]. Our patient had significant hypocalcemia and PHP, unlike previously reported patients from India. The first patient reported from India by Moirangthem et al [7] had mildly elevated PTH and associated vitamin D deficiency. Primary failure of tooth eruption has been reported with PTH1R variants, but these reports did not describe other skeletal and biochemical abnormalities in detail [14, 15]. Our patient also had failure of tooth eruption, consistent with previously published reports. The limited number of reported ES cases may reflect that researchers have identified PTH1R variants with atypical skeletal, dental, and biochemical features but have not linked them to disease without clear pathogenic mechanisms [16]. The heterogenous presentation of PTH1R variants and the resulting confusion led to the name change from PHP to inactivating PTH/PTHrP signaling disorder to increase awareness and understanding of the spectrum [10, 17]. The p.Ala234Thr variant we reported has not been reported previously, and the other 2 patients with ES and PTH resistance have variants within the same second transmembrane domain (p.Ile237Asn and p.Asp241Glu) of PTH1R [8, 9]. The presence of 3 homozygous variants (including this patient) clustered within an 8-amino acid segment (codon 234-241) in transmembrane domain 2 of PTH1R, leading to a similar phenotypic presentation, supports the hypothesis that this region plays an important role in receptor activation and ligand-dependent signaling.

Our case highlights the diagnostic complexity of PHP and skeletal dysplasia in patients with pathogenic PTH1R variants. Many patients with skeletal dysplasia may be misdiagnosed or missed without appropriate genetic screening. The spectrum of skeletal and biochemical abnormalities varies widely across PTH1R variants, compounding the diagnostic challenge. Further functional studies and cell culture assays of PTH1R variants are needed to elucidate the precise role of this receptor in skeletal metabolism.

Learning points

• Eiken syndrome may mimic PHP both clinically and biochemically.

• Eiken syndrome should be considered in patients with PTH resistance and skeletal dysplasia, which has a different genetic basis than PHP.

• Basal ganglia calcification, seizures, deafness, and dental abnormalities are observed in different phenotypes of PTH1R-related disorders.

• Eiken syndrome has characteristic skeletal abnormalities that provide crucial diagnostic clues prior to genetic confirmation.

Contributors

All authors made an individual contribution to authorship. C.V.S.M., A.G., A.B., and K.V.S.H.K. were involved in the patient's diagnosis and management. D.P. and L.A.V.A. were involved in genetic testing and image preparation. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed patient consent for publication

Signed informed consent obtained directly from the patient's relatives or guardians.

Data availability

Original data generated and analyzed for this case report are included in this published article.