Pseudopseudohypoparathyroidism

Disease definition

The term PHP (Online Mendelian Inheritance in Man, OMIM) #103580 for PHP type 1A (PHP1A), #603233 for PHP type IB (PHP1B) and #612462 for PHP type 1C (PHP1C)) describes disorders that share common biochemical features of hypoparathyroidism (that is, hypocalcaemia and hyperphosphataemia) that are the result of resistance of target tissues to the biological actions of parathyroid hormone (PTH). Patients with PHP1A and PHP1C are also characterized by the variable expression of a collection of physical features, termed Albright hereditary osteodystrophy (AHO). Furthermore, based on the number of AHO features and the presence and extent of ectopic ossifications, patients might be classified as having pseudopseudohypoparathyroidism (PPHP; OMIM #612463), progressive osseous heteroplasia (POH; OMIM #166350) or osteoma cutis. Acrodysostosis (OMIM #101800) refers to a group of chondrodysplasias that resemble PHP in some patients, owing to the presence of brachydactyly and often resistance to different hormones, but differ from PHP owing to more extensive facial dysmorphism, nasal hypoplasia and often developmental delay.

Note: recently, a new nomenclature and classification of these heterogeneous but overlapping diseases has been proposed, referring to these disorders as inactivating PTH/PTHrP Signalling Disorders (iPPSDs): Thiele S et al. From Pseudohypoparathyroidism to inactivating PTH/PTHrP Signalling Disorder (iPPSD), a novel classification proposed by the European EuroPHP network. Eur J Endocrinol. 2016 Dec; 175 (6): P1-P17. PubMed PMID: 27401862.

 

Epidemiology

The exact prevalence of PHP is unknown. Studies published in 2000 and 2016 estimated the prevalence to be 0.34 in 100,000 in Japan and 1.1 in 100,000 in Denmark. The prevalence of POH has never been estimated. However, it seems to be extremely rare, as <60 cases have been reported worldwide up to December 2016. The prevalence of Acrodysostosis is unknown as clinical, biochemical and radiological features overlap with those of PHP1A and PPHP.

Clinical description

All forms of PHP can present in infancy, especially if significant hypocalcemia occurs. Symptoms related to low levels of calcium can include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms).Some forms of PHP may remain unnoticed if patients do not have hypocalcemia and/or characteristic physical features, which include short stature, rounded face, short neck, brachydactyly, ectopic ossifications and other poorly defined abnormalities, collectively termed Albright hereditary osteodystrophy (AHO). In some patients, the physical features of AHO might be present in the absence of hormone resistance. Patients with extensive and deep ectopic ossifications are classified as progressive osseous heteroplasia (POH). Other features have been attributed to these disorders since their identification, such as intrauterine growth failure, early-onset obesity (that is, development in the first few months of life and full expression before the end of infancy), hypothyroidism due to resistance to thyroid stimulating hormone (TSH), hypogonadism, growth hormone (GH) deficiency and cognitive impairment, including developmental delay and loss of intellectual function. In acrodysostosis brachydactyly is usually more marked and is associated with more extensive facial dysmorphism, nasal hypoplasia and often developmental delay, in addition to frequent resistance to PTH and TSH.

Etiology

All patients with PHP and PHP-related disorders in whom a molecular diagnosis is confirmed have genetic or epigenetic alterations in genes encoding for proteins involved in the PTH/PTHrP signaling pathway. PHP1A, PPHP and POH are due to genetic defects in the gene coding the alpha sub-unit of the stimulatory G protein (GNAS, 20q13.2-q13.3). The pattern of inheritance is consistent with a tissue-specific paternal imprinting of the gene causing the disease. Patients with PHP1B show an alteration of the methylation pattern of the GNAS locus. Those with the autosomal dominant form of PHP1B often display a recurrent 3-kb deletion in the STX16 gene (20q13.32). Patients with Acrodysostosis display mutations within either the PRKAR1A or the PDE4D genes.

Diagnostic methods

The diagnosis is based on the presence of characteristic clinical and endocrinological findings.
When the clinical pattern is highly suggestive of alteration of a specific gene, Sanger sequencing of that gene is proposed. When the clinical presentation is not suggestive of a specific gene, a targeted gene panel encompassing genes that encode proteins involved in the PTH–parathyroid hormone-related protein (PTHrP) signalling pathway might be performed. The parental origin of the variant could have important clinical implications; thus, parental testing is indicated when a genetic alteration is detected. Methylation analysis of the GNAS locus by MS-MLPA is indicated in those cases with isolated hormone resistance and/or mild bone phenotype.

Differential diagnosis

Differential diagnoses of PHP and related disorders based on the main clinical presentation

Leading symptom Differential diagnosis Associated signs or comments
Hypocalcaemia with elevated PTH Vitamin D deficiency or resistance – Improvement upon vitamin D therapy
– Rickets, alopecia
Rickets – Enlargement of the metaphyses
– Leg bowing
– Elevated ALP
Hypoparathyroidism due to a mutation in the PTH gene Use different assays to confirm the elevated PTH
Brachydactyly Tricho-rhino-phalangeal syndrome due to TRPS1 mutations – Dysmorphism: slowly growing and sparse scalp hair, laterally sparse eyebrows, bulbous tip of the nose, long flat philtrum, thin upper vermillion border and protruding ears
– Hip dysplasia, small feet and a short hallux, exostosis and ivory epiphyses
Isolated brachydactyly type E due to HOXD13 mutations – Syndactyly, long distal phalanges and shortening of the distal phalanx of the thumb
– Hypoplasia/aplasia, lateral phalangeal duplication and/or clinodactyly
Brachydactyly mental retardation syndrome due to 2q37 microdeletions – Obesity, short stature
– Brachydactyly
– Psychomotor and cognitive alterations
Turner Syndrome due to partial or complete loss of one X chromosome – Short stature, low birth weight, gonadal failure, and variable neurocognitive defects
– Brachydactyly and Madelung deformity
Brachydactyly type E with short stature due to PTHLH mutations – Short stature of variable severity, impaired breast development
– Oligodontia, delayed tooth eruption, dental malposition
– Pseudoepiphyses, brachydactyly

Ossifications- Subcutaneous

 

Acne vulgaris  

Cutaneous tumors such as primarily pilomatricomas, chondroid syringomas, basal cell carcinomas, pilar cysts and nevi

Secondary or traumatic osteoma cutis and miliary ostoma

 
Inflammatory conditions such as scars, chronic venous stasis, morphea, scleroderma, dermatomyositis, and myositis ossificans progressiva  
Ossifications- Progressive

Fibrodysplasia Ossificans Progressiva due to a recurrent activating missense mutation of ACVR1

– Progressive ossification of skeletal muscle, tendons, fascia and ligaments
– Upper back and neck are the first parts of the skeleton to be affected; trauma alters the natural progression of the disease
– Congenital malformation of the great toes

Tumoral calcinosis

Due to FGF23 or GALNT3 mutations

– Deposition of calcium within the skin and/or muscles
– Hyperphosphataemia
Early-onset obesity Beckwith-Wiedemann syndrome – Hemihypertrophy
– Macroglossia

Genetic, cytogenetic or syndromic anomalies associated with early onset obesity, including:

– Prader-Willi syndrome

– Monogenic obesity (mutations in POMC, MC4R, leptin, leptin receptor)

 

Early onset hypothyroidism

 

Congenital hypothyroidism of any cause – Small thyroid in size, in place
– TSH moderately elevated
TSH resistance due to mutations in the TSH receptor  
Hypertension Autosomal dominant hypertension and brachydactyly type E syndrome Short stature

Antenatal diagnosis

There are very few cases with antenatal diagnosis of PHP or PPHP, as their clinical manifestations are usually not specific within this period. The bone dysplasia observed in patients with acrodysostosis might display a prenatal onset, mostly when caused by PRKAR1A mutations.

Genetic counseling

PHP can be sporadic or inherited autosomal dominantly with parental imprinting. In inherited cases, genetic counseling is possible.

Management and treatment

A multidisciplinary follow-up and early, specific interventions are necessary for efficient therapeutic management of these patients.
Management consists of general measures (lifestyle advice for obesity, exercise and rehabilitation) and specific measures aimed to correct hypocalcemia, growth retardation and other endocrine deficiencies. Surgical management may include orthopaedic, spinal and dental aspects.

Prognosis

Very variable depending on age at onset, severity and presence or absence of endocrine abnormalities..

For patients

DO: Seek a specialist who has experience in treating people with rare disease of mineral metabolism. Do connect with patients groups on Facebook or social media.

Expert reviewer

G Mantovani

Font link

Mantovani G et al., Diagnosis and management of Pseudohypoprathyroidism and related disorders: first international consensus statement. Nat Rev Endocrinol. 2018 14(8):476-500. doi: 10.1038/s41574-018-0042-0. Review. PubMed PMID: 29959430