Pseudopseudohypoparathyroidism (PPHP), a very rare disorder initially described more than 50 years ago, stems from a genetic phenomenon known as "genomic imprinting", where the expression of mutated genes differs for maternal and paternal transmission [1] [2] [3]. Namely, PPHP is a subtype of Albright's hereditary osteodystrophy (AHO), an autosomal dominant disease that develops due to mutations of the genes encoding the α subunit of the Gs protein (GNAS1) located on chromosome 20 [1] [4]. If this mutation is transferred from the chromosome of the mother, pseudohypoparathyroidism (PHP) type 1a will develop, but if paternal transmission occurs, children suffer from pseudopseudohypoparathyroidism [1] [5] [6] [7] [8]. The clinical presentation is practically identical for both forms - a short stature with reduced growth of metacarpal and metatarsal bones (manifesting as shorter fingers and toes, or brachydactyly), as well as obesity and a round face [1] [4]. However, the distinguishing feature of PPHP is normal circulating levels of parathyroid hormone (PTH) and its unchanged activity in the kidneys, which in the case of PHP leads to hypocalcemia and hyperphosphatemia [9]. Rare reports have described the appearance of cardiac arrhythmias (atrioventricular blocks) and syncope in these patients [9].

• Short Stature

  She also exhibited a short stature, round face and brachydactyly with shortening of the metacarpal and metatarsal bones. The serum levels of calcium, phosphorus and PTH were normal. [doi.org]

  Further observations are necessary to define the frequency and significance of GH deficiency and the role of GH replacement therapy in pseudohypoparathyroidism- and PPHP-associated short stature. [ncbi.nlm.nih.gov]

  Short stature may be present. Obesity is less common in pseudopseudohypoparathyroidism than in pseudohypoparathyroidism. Osteoma cutis may be present. [en.wikipedia.org]

• Malocclusion

  The physical examination yielded a height of 135 cm (5 th percentile for a normal Korean girl), a round face, malocclusion of teeth and shortened left 4 th and 5 th fingers and 4 th toe ( Fig. 1 ). [doi.org]

• Calcinosis Cutis

  Early manifestation of obesity and calcinosis cutis in infantile pseudohypoparathyroidism Preamrudee Poomthavorn Department of Endocrinology and Diabetes, The Royal Children s Hospital, Melbourne, Victoria, Australia J Paediatr Child Health 42:821-3. [labome.org]

• Skeletal Dysplasia

  Although synovial manifestations of other rare skeletal dysplasias have been reported, the association of synovial osteochondromatosis and PPH has not been described. 28,29 Because synovial osteochondromatosis and PPH share in common a disorder of soft [healio.com]

• Coxa Valga

  valga; and genu valgum. [ncbi.nlm.nih.gov]

• Bowing of The Long Bones

  Common musculoskeletal anomalies associated with PPH include shortening/bowing of long bones; shortening of metacarpals, metatarsals, and/or phalanges; exostoses; calcification/ossification of subcutaneous and/or periarticular soft tissues; a thickened [healio.com]

• Round Face

  She also exhibited a short stature, round face and brachydactyly with shortening of the metacarpal and metatarsal bones. The serum levels of calcium, phosphorus and PTH were normal. [doi.org]

  She was 153 cm tall and weighed 109 kg with a round face. [endocrine-abstracts.org]

  A 62 year old man with a height of 171.5 cm, a round face, a short neck, central obesity and brachydactyly had normal ranges of serum calcium, phosphorus and PTH and a normal Ellsworth-Howard test. [e-enm.org]

  Abstract In 1942 Albright, Burnett, Smith, and Parson 1 originated the term pseudohypoparathyroidism (PH) to describe a group of patients with round face, short stature, short metacarpals and metatarsals, ectopic ossifications, elevated serum phosphorus [annals.org]

• Short Neck

  A 62 year old man with a height of 171.5 cm, a round face, a short neck, central obesity and brachydactyly had normal ranges of serum calcium, phosphorus and PTH and a normal Ellsworth-Howard test. [e-enm.org]

• Myelopathy

  […] blood transfusion complicated with pseudopseudohypoparathyroidism. ( 12413020 ) Yoshida Y....Osame M. 2002 19 STK25 is a candidate gene for pseudopseudohypoparathyroidism. ( 11543625 ) Davids M.S....Melnick M.B. 2001 20 [A case of HTLV-1 associated myelopathy [malacards.org]

  [A case of HTLV-1 associated myelopathy (HAM) with pseudopseudohypoparathyroidism] J Fujita Department of Neurology, Tachikawa Hospital Rinsho Shinkeigaku 40:611-3. 2000 We report a case of HTLV-1 associated myelopathy (HAM) with pseudopseudohypoparathyroidism [labome.org]

  Multilevel myelopathy associated with pseudohypoparathyroidism simulating diffuse skeletal hyperostosis: a case report and literature review. Spine. 2010; 35 (23):E1355–8. [ PubMed ] [ Google Scholar ] 41. van Lindert EJ, Bartels RH, Noordam K. [ncbi.nlm.nih.gov]

• Limb Weakness

  A 42 year old Greek male with pseudo-pseudohypoparathyroidism presented with difficulty in walking and with lower limb weakness. [ncbi.nlm.nih.gov]

• Polyradiculoneuropathy

  The neuropathy is thought to be similar to chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); however, the relationship, if any, between PPHP and CIDP is unknown. [ncbi.nlm.nih.gov]

The rare occurrence of pseudopseudohypoparathyroidism in clinical practice might present a challenge for the physicians when attempting to make the diagnosis, which is why the initial interview with the patient is crucial. In fact, the autosomal dominant pattern of inheritance mandates a positive family history, particularly from fathers who are responsible for PPHP transmission to their children, thus this piece of information may be essential for making a presumptive diagnosis [7]. Furthermore, the father should be examined as well, given the fact that they will universally present with the same signs and symptoms [8]. After a detailed physical examination that will ensure identification of skeletal-related findings, a full biochemical workup should be the next step, where serum electrolyte assessment reveals normal serum calcium and phosphate levels, whereas hormonal evaluation shows parathyroid hormone (PTH) levels within physiological limits. These findings will further point toward pseudopseudohypoparathyroidism but in order to establish a definite diagnosis, genetic testing to confirm GNAS gene mutations (both in the parents and in the affected patients) is necessary [1] [9].

• Gliosis

  Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification. [ncbi.nlm.nih.gov]

1. Simpson C, Grove E, Houston BA. Pseudopseudohypoparathyroidism. Lancet. 2015;385(9973):1123.
2. Kottler ML, Linglart A, Carel JC. Albright hereditary osteodystrophy. Orphanet Encyclopedia 2004. https://www.orpha.net/data/patho/GB/uk-AHO.pdf
3. Wilson LC, Hall CM. Albright's hereditary osteodystrophy and pseudohypoparathyroidism. Semin musculoskelet Radiol 2002;2013:273–83.
4. Hamasaki H, Mukaino T, Kaneko H, et al. Journal of Endocrinology and Metabolism. 2013:3(6):150-152.
5. Turan S, Bastepe M. GNAS spectrum of disorders. Curr Osteoporos Rep. 2015;13(3):146-158.
6. Davies AJ, Hughes HE. Imprinting in Albright’s hereditary osteodystrophy. J Med Genet. 1993;30:101–103.
7. Wilson LC, Oude-Luttikhuis MEM, Clayton PT, et al. Parental origin of Gsα gene mutations in Albright’s hereditary osteodystrophy. J Med Genet. 1994;31:835–839.
8. Lemos MC, Thakker RV. GNAS Mutations in Pseudohypoparathyroidism Type 1a and Related Disorders. Hum Mutat. 2015;36(1):11-19.
9. Rahmat N, Venables P. Sinus pauses and high-grade atrioventricular block in Albright’s hereditary osteodystrophy with pseudopseudohypoparathyroidism. BMJ Case Rep. 2013;2013:bcr2013010116.