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]

  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. [symptoma.com]

  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]

  stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. [search.com]

• 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]

• Piebaldism

  Crouzon syndrome, Jackson–Weiss syndrome ) FGFR3 ( Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome ) INSR ( Donohue syndrome Rabson–Mendenhall syndrome ) NTRK1 ( Congenital insensitivity to pain with anhidrosis ) KIT ( KIT Piebaldism [en.wikipedia.org]

• Anhidrosis

  […] syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson–Weiss syndrome ) FGFR3 ( Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome ) INSR ( Donohue syndrome Rabson–Mendenhall syndrome ) NTRK1 ( Congenital insensitivity to pain with anhidrosis [en.wikipedia.org]

• Severe Short Stature

  A case is presented of a prepubertal girl with the characteristic somatic features of Albright's hereditary osteodystrophy, including severe short stature, cataracts and shortening of all metacarpals and metatarsals and of the second middle hand phalanges [ncbi.nlm.nih.gov]

• 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

  AHO is associated with characteristic developmental abnormalities that include a short stocky stature, a short neck, brachydactyly, a round face, central obesity, mental retardation and subcutaneous ossifications. [e-enm.org]

  […] metacarpal Shortened long bone of hand 0010049 Short metatarsal Short long bone of foot 0010743 Short neck Decreased length of neck 0000470 Short stature Decreased body height Small stature [ more ] 0004322 Showing of 18 | Last updated: 5/1/2019 Diagnosis [rarediseases.info.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].

Our patient is the first described case of PPHP associated with idiopathic GH deficiency, and the second report of long-term GH treatment in a subject with PPHP. [ncbi.nlm.nih.gov]

Pseudopseudohypoparathyroidism Specialty Rheumatology, medical genetics, endocrinology Usual onset Before birth Duration Lifetime Differential diagnosis Pseudohypoparathyroidism, hypoparathyroidism, Albright's hereditary osteodystrophy Treatment Treatments [en.wikipedia.org]

Pseudopseudohypoparathyroidism symptoms, causes, diagnosis, and treatment information for Pseudopseudohypoparathyroidism (Vitamin D resistant rickets) with alternative diagnoses, full-text book chapters, misdiagnosis, research treatments, prevention, and prognosis [search.com]

Prognosis Pseudo-PHP is not life threatening but quality of life can be affected in those with severe ectopic ossification. The documents contained in this web site are presented for information purposes only. [orpha.net]

- administration of 3 doses of 100 000 UI Stoß vitamin D2 or D3 intramuscularly every 3 days, then a dose of 200 000 IU after 30 days oral or i.m. 37 Rickets:Evolution and prognosis Evolution is generally favorable when rickets is controlled. [slideplayer.com]

Etiology The disease is caused by paternally inherited heterozygous molecular defects in the GNAS gene (20q13) encoding the alpha sub-unit of the stimulatory G protein (Gs alpha), which results in a reduction in the expression/activity of Gs alpha. [orpha.net]

Hypocalcemia may occur at certain stages of rickets (I and III). 46 Tetania- etiological classification II. [slideplayer.com]

It is suggested that the ratio of width to length of the thumbnail be included in the physical examination of children with convulsions of unknown etiology, in an effort to identify more patients with pseudo-hypoparathyroidism. [pediatrics.aappublications.org]

Epidemiology and Diagnosis of Hypoparathyroidism. J Clin Endocrinol Metab. 2016 Jun. 101 (6):2284-99. [Medline]. [Full Text]. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. [emedicine.medscape.com]

Summary Epidemiology Prevalence is unknown but series of patients usually include one patient with pseudo-PHP for every two patients with PHP 1a (see this term). [orpha.net]

Journal of epidemiology /Japan Epidemiological Association. 2000; 10 (1):29–33. [ PubMed ] [ Google Scholar ] 3** Landreth H, Malow BA, Shoemaker AH. Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a. [ncbi.nlm.nih.gov]

[…] other conditions: Hormone resistance is not present in pseudopseudohypoparathyroidism. [5] Short stature may be present. [6] Obesity is less common in pseudopseudohypoparathyroidism than in pseudohypoparathyroidism. [7] Osteoma cutis may be present. [8] Pathophysiology [ipfs.io]

Pseudopseudohypoparathyroidism and pseudohypoparathyroidism both involve the same GNAS gene, [8] but pseudopseudohypoparathyroidism has normal calcium homeostasis because of the normal maternal allele in the kidney. [9] Pathophysiology [ edit ] The GNAS1 [wikivividly.com]

[citation needed] Pseudopseudohypoparathyroidism and pseudohypoparathyroidism both involve the same GNAS gene,[8] but Pseudopseudohypoparathyroidism has normal calcium homeostasis because of the normal maternal allele in the kidney.[9] Pathophysiology [en.wikipedia.org]

[…] pseudopseudohypoparathyroidism.htm Pseudopseudohypoparathyroidism symptoms, causes, diagnosis, and treatment information for Pseudopseudohypoparathyroidism (Vitamin D resistant rickets) with alternative diagnoses, full-text book chapters, misdiagnosis, research treatments, prevention [search.com]

[…] a therapeutic effect while avoiding adverse effects that: hypercalcemia, hypercalcuria. 35 Treatment Lifestyle and nutrition It is important in the treatment and prevention of rickets triggered the disease. [slideplayer.com]

Intraoperatively, periarticular calcification or ossification of the joint capsule and collateral ligaments may prevent soft tissue balance of the knee. In our patient, a varus-valgus constrained implant was required. [healio.com]

Genetic testing for a mutation in the GNAS1 gene can confirm diagnosis and identify subtype. [1] The goals of pharmacotherapy are to correct calcium deficiency, prevent complications, and reduce morbidity. [emedicine.medscape.com]

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.