Pseudohypoparathyroidism with Ectopic Calcification and 22q11 Deletion Syndrome: A Rare Case

Abstract

Ectopic calcification in soft tissue is associated with several disorders including pseudohypoparathyroidism (PHP), which is characterized by resistance or nonresponse to parathyroid hormone (PTH) function. Association between PHP and 22q11DS, also known as DiGeorge syndrome, is rare, especially in children. We describe a newborn girl diagnosed with 22q11DS, presenting ectopic calcifications in soft tissue and suspicion of PHP. PTH function showed values close to the upper limit of the reference value. Radiology showed bone callus in the right wrist. PHP can be a new clinical finding associated with 22q11DS. Parathyroid function investigation in individuals with 22q11DS, presenting bone dysmorphisms and/or calcium metabolism alterations, should be considered.

Introduction

Ectopic calcifications in soft tissue occur sporadically or as a rare genetic condition and may be associated with fibrodysplasia ossificans progressiva (FOP; OMIM 135100), progressive osseous heteroplasia (POH; OMIM 166350), pseudohypoparathyroidism, type 1A/Albright hereditary osteodystrophy (PHP1A/AHO; OMIM 103580), hyperphosphatemic familial tumoral calcinosis (HFTC; OMIM 211900), normophosphatemic familial tumoral calcinosis (OMIM 610455), and pseudohypoparathyroidism (PHP; OMIM 203330). ¹

PHP is characterized by resistance to parathyroid hormone (PTH). Due to differences in pathogenesis and phenotype, PHP can be classified into four types: Ia, Ib, Ic, and II. ^{2 3} Pseudo-pseudohypoparathyroidism (pseudo-PHP) is a PHP variant characterized by the development of isolated AHO without hormonal resistance. Pseudo-PHP is caused by mutations in the GNAS gene through paternal inheritance and it is genetically related to PHP-Ia. Signs and symptoms of both conditions are similar; however, individuals with pseudo-PHP do not show resistance to PTH while individuals with PHP-Ia do. ⁴

The diagnosis of PHP type Ia (PHP1a) is challenging since clinical features such as osteodystrophy, brachydactyly, round face, and symptomatic hypocalcemia, are generally developed after childhood. Although ectopic calcification may be an early sign of PHP1a, there is no well-established evidence in the beginning of its development. ^{2 3}

22q11 deletion syndrome (22q11DS, OMIM 611867), also known as DiGeorge syndrome, is caused by a microdeletion (1.5–3 Mb) on chromosome 22 and has an estimated prevalence of 1 per 4,500 live births. ⁵ Phenotypic presentation is variable and endocrinopathies are commonly observed in patients with this deletion. Generally, 22q11DS can be diagnosed when the individual presents congenital heart diseases associated with other clinical manifestations. The spectrum of clinical features that compose 22q11DS has become well characterized and some endocrine abnormalities such as growth hormone deficiency and hypothyroidism have been reported. However, the association between 22q11DS and PHP is rare. ^{6 7} We report a girl, diagnosed with 22q11DS, with ectopic calcifications in soft tissues and suspicion of PHP.

Case Description

We report a 2-month and 13 day-old girl with a history of congenital heart disease, presence of ectopic calcifications in soft tissues (periosteal region), and facial dysmorphism. The proband was the first child of young and nonconsanguineous parents, with a healthy maternal half-sister. Pregnancy was uneventful and the prenatal serologies were negative. The mother denied smoking or alcohol intake during pregnancy. The child was born by cesarean section at 39 weeks and 5 days of gestation, weighing 2,630 g, with meconium-stained amniotic fluid and Apgar scores of 8 and 10. The patient evolved with desaturation, requiring orotracheal intubation. She was immediately transferred to the neonatal intensive care unit. Her neonatal period was complicated with several episodes of sepsis that were treated by antibiotic therapy. Echocardiogram showed double outlet right ventricle with severe pulmonary hypoplasia and minimal ductus arteriosus persistence (patent ductus arteriosus [PDA]).

Neonatal screening revealed a subclinical hypothyroidism (thyroid stimulating hormone [TSH] 14.8 uUl/mL [VR 0.85–6.15 uUl/mL] and T4 1.28 mg/dL [VR 0.94–1.44 mg/dL]), hypocalcemia that remained in the following dosages (total calcium [CaT] 8.6 mg/dL; 6.6 mg/dL; 8.3 mg/dL [VR 8.7–10.5 mg/dL]) and calciuria (CaT 11 mg/L; 29 mg/L; 177 mg/L). Creatinine (<0.1 mg/dL) and urea (28 mg/dL) levels were normal. Renal diseases and immunoglobulinopathies were excluded. Sodium (140 mEq/L [VR 132–146 mEq/L]), potassium (4.9 mEq/L [reference value (RV) 3.5–5.5 mEq/L]), magnesium (2.1 mg/dL [RV 1.6–2.4 mg/dL]), ionic calcium (4.8 mg/dL [RV 4.0–4.8 mg/dL]), serum inorganic phosphorus (5.6 mg/dL [VR 3.5–6.6 mg/dL]), glucose (82 mg/dL [VR 70–99 mg/dL]), and 25-hydroxy vitamin D (27 ng/mL, [VR >20 ng/mL]) dosages were normal. Hormonal investigation of parathyroid function (PTH) initially showed values close to the limit of the reference value (PTH 77 pg/mL; 85.2 pg/mL [VR 18–88 pg/mL]). After supplementation with calcium phosphate, cholecalciferol, and calcitriol, PTH levels were elevated (156.8 pg/mL).

Physical examination revealed bone callus in the right wrist. Radiological examinations showed no morphological or structural alterations in the skull and face, cervical spine, dorsal spine, or sacral loin. However, a double cortical contour was observed in the proximal third of both femurs, suggesting cortical hyperostosis or periosteal calcification along the femoral diaphysis. Dysplasia of the left acetabular ridge was also observed, as well as signs of osteopenia in the long bones, upper and lower limbs, and pelvis. Signs of osteopenia were noticed in both hands and wrists. Ectopic calcifications in soft tissues were observed in the distal end of the right forearm, in the wrist bones and in the proximal end of the metacarpal ( Fig. 1 ).

Fig. 1.

Ectopic calcification in the right wrist evidenced on radiography.

High-resolution karyotype showed a normal female chromosomal constitution (46,XX). Molecular cytogenetic testing by fluorescent in situ hybridization using the commercial Vysis LSI DiGeorge/TUPLE1 (Abbot Molecular) dual color probe set showed a deletion of 22q11.2.

At 8 months of age, the patient was readmitted for bronchiolitis. Dosages of PTH levels remained elevated (123.7 pg/mL). Pathogenesis evaluation of hypocalcemia revealed repeatedly high or normal levels of PTH, which was consistent with the diagnosis of PHP. The proband was submitted to a correction surgery for her congenital heart disease. While being operated, the proband had an episode of cardiac arrest and remained on mechanical ventilation by tracheostomy, developing a severe neurological condition. She passed away on the same day. Thus, the patient was diagnosed with 22q11DS and with presence of ectopic calcifications that could be associated with PHP.

Discussion

This report aimed to show a newborn girl diagnosed with 22q11DS and suspicion of PHP. The suspicion was raised due to hypocalcemia and increased levels of PTH along with ectopic calcifications in soft tissues.

PHP is a rare condition characterized by resistance or nonresponse to PTH that may have normal and/or increased serum levels. ⁶ As for the PHP type, biochemical and hormonal values verified in our case corroborate with the results found in other studies where the cases are diagnosed with PHP1a. Also, presence of hyperphosphatemia was not always evidenced ( Table 1 ). PHP1a is also known as AHO and has a variety of clinical findings such as short stature, mental retardation, short metacarpals and obesity. During childhood, the clinical manifestations of PHP1a are normally subtle and, therefore, tend to be easily ignored. ⁶ Due to patient's death in the first month, it was not possible to identify dysmorphologies compatible with AHO.

Table 1. Clinical findings for PHP1a: our case and literature case reports.

Study	Patient age	Clinical findings for PHP1a
		Seizures	Calcemia (N, ↑, ↓)	Hyperphosphatemia	Hypothyroidism	PTH (N, ↑, ↓)	TSH (N, ↑, ↓)	Ectopic calcification	AHO confirmed
Our case	2 mo and 13 d		↓		x	↑	↑	x
Liu et al 6	14 y	x	↓	x		N	N	x
Adachi et al 8	P1: 13 d P2: 9 d		N			↑	N	x
			N		x	N	N	x
Riepe et al 9	7 mo					↑		x	x
Lubell et al 10	2 y		N	x	x	↑	↑	x	x
Zung et al 11	3 y		N			↑	↑	x	x

Abbreviations: ↑, high; ↓, low; AHO, Albright hereditary osteodystrophy; N, normal; P, patient; PHP1a, pseudohypoparathyroidism, type 1a; PTH, parathyroid hormone; TSH, thyroid stimulating hormone.

Some individuals diagnosed with PHP1a have resistance to other hormones besides PTH, normally TSH and gonadotropins. Resistance to TSH, clinically indistinguishable from primary hypothyroidism, may become apparent before hypocalcemia and, occasionally, can be diagnosed through neonatal metabolic screening. The resistance to PTH and TSH is a possible explanation to justify the suspicion of PHP1a in our case. ¹² Although ectopic calcification may be an early sign of PHP1a, there is no clear description about when it starts to develop. However, patients diagnosed with PHP1a and presence of subcutaneous calcification in the neonatal period have been reported. ^{8 9}

Association between 22q11DS and PHP in children is rare, mainly due to the variety of clinical features. ^{6 7} Abnormal parathyroid function was the first hormonal disorder related in 22q11DS: from a severe neonatal hypocalcemia to subclinical PTH failure. 22q11DS has an estimated prevalence of 1 per 4,500 live births and it is the most common autosomal deletion syndrome. In total, 30 to 50 genes are located in the deleted region of chromosome 22q11.2, which includes several transcription factors, that regulate thymus and parathyroid development. ^{6 7} The limited number of reports associating PHP and 22q11DS is mainly due to the location of the Gs-a protein on chromosome 20. However, Craigen raised the hypothesis that a more extensive deletion of chromosome 22 may lead to PHP due to the haploinsufficiency of protein G. This haploinsufficiency would be a consequence of a Gs-alpha protein locus adjacent to the critical region of chromosome 22. Heterozygous mutations in the GNAS gene are the main cause of Gsa protein-reduced activity. ⁹ Liu et al described a patient diagnosed with 22q11DS that had a wide phenotypic spectrum with multiple dysmorphisms. The authors suggested, that when an individual is diagnosed with PHP, 22q11DS should be considered. It is not impossible that 22q11DS occurs simultaneously with PHP. ⁶

Different age groups, diagnosed with PHP have been reported ( Table 1 ). Therefore, it is important to note that the investigation for PHP, which may or may not be associated with 22q11DS, should be considered in all patients with hypocalcemia, independently of their age. PHP may be underdiagnosed in patients with 22q11DS since hormonal (hyper/hypothyroidism) and mineral (hypocalcemia) disorders are common in these individuals. ⁶ However, ectopic calcifications are usually evidenced in PHP. ³ Considering that the 22q11 region includes several transcription factors that regulate thymus and parathyroid development, we suggest that individuals diagnosed with 22q11DS and with bone dysmorphisms should be considered for parathyroid abnormal function investigation. Therefore, PHP could be a new clinical finding associated with 22q11 deletion.

Funding Statement

Funding This study was supported by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, 17/2551-0001063-9), Programa de Extensão Universitária do Ministério da Educação e Cultura (PROEXT), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, 001)/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 301834/2016-4).