Uvod: pseudohipoparadtireoidizam (PHP) je sindrom hormonske rezistencije koji je prvi opisao Albright sa saradnicima1942. godine. Svi ovi pacijenti su imali.
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Danica Stamenković-Pejković1,2, Ana Gligić2, Goran Cvijović1,2, Svetlana Zorić2, Danka Jeremić A2, Snežana Polovina2, Aleksandra Kendereški1,2, Dragan Micić1, Mirjana Šumarac-Dumanović1,2
PSEUDOPSEUDOHIPOPARATIREOIDIZAM ILI ALBRAJTOVA HEREDITARNA OSTEODISTROFIJA LIKE SYNDROME
Kratak sadržaj Uvod: pseudohipoparadtireoidizam (PHP) je sindrom hormonske rezistencije koji je prvi opisao Albright sa saradnicima1942. godine. Svi ovi pacijenti su imali visok nivo PTH i specifične skeletne deformitete koji su kasnije označeni kao Albrightova hereditarna osteodistrofija (AHO). PTH svoje efekte ostvaruje preko alpha subjedinice G proteina. GNAS 1 gen kodira sintezu alpha subjedinice G proteina i molekularni defekti na nivou ovog gena dovode do nastanka najmanje 4 različita oblika ovog sindroma. Pseudopseudohipoparatireoidizma (PPHP) je forma PHP koja se karakteriše prisustvom fenotipskih karakteristika AHO, ali bez rezistencije na delovanje PTH. Albrightova hereditarna osteodistrofija like syndrome (AHO like syndrome) ima neke zajedničke karakteristike sa AHO ali ovaj sindrom nije povezan sa molekularnim defektima u GNAS 1 genu. Prikaz slučaja: prikazali smo pacijentkinju sa fenotipskim karakteritikama AHO (brahidaktilija, nizak rast, intelektualni deficit, genu varum) ali bez rezistencije na delovanje PTH. PPHP se uglavnom javlja u porodicama u kojima postoji PHP tip 1a i prenosi se od oca što nije slučaj kod naše pacijentkinje. Postoji teoretska mogućnost da je mutacija na nivou GNAS 1 gena kod pacijentkinje nastala de novo ali bez genetskog testiranja, u ovom slučaju, nije moguće isključiti prisustvo 2q37 delecije odnosno dijagnozu AHO like syndroma.
Medicinski fakultet Univerziteta u Beogradu.
1
Klinika za endokrinologiju, dijabetes i bolesti metabolizma, Klinički centar Srbije, Beograd.
2
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Zaključak: u nekim slučajevima PPHP potrebno je razmotriti diferencijalno dijagnostički AHO like syndrome, ali jedini način u takvim situacijama je genetsko testiranje. Klučne reči: pseudopseudohypoparatireoidizam, Albrajtova hereditarna osteodistrofija, Albrajtova hereditarna osteodistrofija like syndrome, GNAS 1 gene
Prikaz slučaja Pacijentkinja stara 18 godina hospitalizovana je pod sumnjom na pseudopseudohipoparatireoidizam radi dopunskog endokrinološkog testiranja. Pacijentkinja je prvo dete iz uredno kontrolisane trudnoće. Rođena je u terminu sa navodno normalnom telesnom težinom. Postnatalni razvoj je bio uredan, ali od rođenja ima skraćenje 4. i 5. prsta leve i desne šake i deformisan i kraći 4. prst desnog stopala. Krive “O” noge ima od ranog detinjstva. Sa polaskom u školu zaostaje u rastu i navodi da je uvek bila najniža u odeljenju. Majka i otac su normalne visine. Zbog problema sa učenjem napustila je dalje školovanje u 5. razredu osnovne škole. Prva menstruacija je bila u 11. godini života. Ciklusi su uvek bili redovni na 30 dana. Navodi normalan razvoj sekundarnih seksualnih karakteristika. Od 10. godine života ima česta izčašenja čašica zbog čega je januara meseca ove godine bila hospitalizovana u Institutu za ortopediju Banjica. Tom prilikom su između ostalog registrovane uredne vrednosti TSH, PTH i jonizovanog kalcijuma. Urađena je osteodenzitometrija koja je pokazala značajno smanjenje koštane gustine (osteoporoza, Z scor vrat butne kosti -2.8 i Z scor L1-L4 -3.3). Pre odluke o hirurškom lečenju levog kolena zbog ponovljenih izčašenja čašice pacijentkinja je upućena endokrinologu radi dalje dijagnostike i lečenja osteoporoze. U ličnoj anamnezi negira druge hronične bolesti. U porodičnoj anamnezi otac i mlađa sestra imaju krive noge (O), majka i starija sestra imaju problem sa čestim izčašenjem čašice kolena, ujak ima kraći IV i V prst šaka. Navodno niko u porodici nije imao problema sa nižim vrednostima kalcijuma u krvi. Objektivno pacijentkinja je nižeg rasta (< 3d percentil) i na donjoj granici za normalnu uhranjenost (TM 37.5 kg, TV 140.5 cm, ITM 18.9 kg/m2). U razgovoru sa pacijentkinjom dobija se utisak prisustva blažeg intelektualnog deficita. Prisutno je skraćenje IV i V prsta obe šake slika 1). Skraćen i deformisan IV prst desnog stopala (slika 2). Pacijentkinja ima izražen stepen genu varum (slika 3). Nalaz po sistemima organa uredan. U rutinskim analizama sve uzete rutinske biohemijske analize u granicama normale uključujući i vrednosti fosfata, jonizovanog kalcijuma, ukupnog kalcijuma i magnezijuma u serumu. Kalciureza u granicama normale. U hormonskim analizama dobijene uredne vrednosti PTH. Vitamin D značajno snižen. T4 i TSH u granicama normale. Kalcitonin uredan. Vrednosti hormona rasta u profilu u granicama normale.
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Slika 1
Slika 2
Slika 3
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Dobijen adekvatan odgovor hormona rasta u ITT-u. Vrednosti FSH, LH, estradiola, testosterona, SHBG, DHEAS, androstendiona u granicama normale. Karitip 46, XX (registrovan je normalan ženski kariotip). Na rtg-u šaka vidi se skraćenje IV i V metakarpalne kosti na obe šake (slika 4). Na rtg-u stopala vidi se skraćenje IV metatarzalne kosti desnog stopala kao i skraćenje IV proksimalne, intermidijarne i distalne falange desnog stopala (slika 5). EHO pregledi abdomena, karlice i štitaste žlezde su bili uredni.
Slika 4
Slika 5
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Diskusija Albright je 1942. god. otkrio sindrom koji je nazvao PHP i tom prilikom je opisao nekoliko pacijenata sa hipokalcijemijom, hiperfosfatemijom i povišenim nivom PTH odnosno rezistencijom na delovanje ovog hormona koji su bili udruženi sa specifičnim koštanim defektima kasnije označenim kao AHO. Primena egzogenog PTH kod ovih pacijenata bila je praćena izostankom očekivane fosfaturije kao i stimulacije renalne produkcije cAMP (1). Molekularni defekti u genu (GNAS1) koji kodira sintezu alfa subjedinice stimulatornog G proteina (Gsα) dovode do nastanka najmanje 4 različita oblika ovog sindroma: PHP Ia, PHP Ib, PHP Ic i PPHP. Sobzirom da nekoliko drugih peptidnih hormona kao što su TSH, ADH, gonadotropini, glukagon, ACTH i GHRH koriste takođe alpha subjedinicu stimultornog G proteina za ostvarivanje svojih efekata neke forme PHP pokazuju i rezistenciju na delovanje ovih hormona pored rezistencije na delovanje PTH (2) . Osnovne karakteristike različitih oblika PHP prikazane su u tabeli 1. Tablela 1. Klasifikacija PHP
AHO
Hormonska rezistencija
Heterotopične osifikacije
PTH infuzija
GNAS defekt
PHP I a
da
PTH, TSH, Gn, GHRH
da površne
↓cAMP ↓ fosfaturija
mutacija majčin alel
PPHP
da
ne
da površne
normalan
očev alel
PHP I b
ne
PTH, TSH
ne
PHP Ic
da
PTH, TSH, Gn
da površne
↓cAMP imprinting ↓ fosfaturija disregulacija ↓cAMP Nekoliko ↓ fosfaturija imprinting m.
Gn-gonadotropini;
Jedan od oblika PHP je PPHP. U jednoj istoj porodici, neki članovi sa molekularnim defektom u GNAS1 genu imaju rezistenciju na delovanje PTH i AHO dok drugi članovi te iste porodice pokazuju iste fenotipske karakteristike u smislu postojanja AHO ali nemaju rezistenciju na delovanje PTH. Prisutvo fenotipskih karakteristika AHO bez znakova rezistencije na delovanje PTH predstavljaju osnovne karakteristike PPHP. Ispitivanja su pokazala da jedna ista mutacija u porodici na nivou GNAS1 gena ako se nasledi od majke dovodi do nastanka PHP 1a, a u koliko se nasledi od oca dovodi do razvoja PPHP. Gsα se sintetiše u većini
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ćelija zahvaljujući prisutvu oba alela (očev i majčin). Međutim u nekim ćelijama kao što su ćelije na nivou proksimalnog renalnog tubula, somatotropne ćelije, tireociti, ćelije gonada, Gsα se primarno sintetiše zahvaljujući majčinom alelu. Fenomen genskog imprintinga podrazumeva selektivnu inaktivaciju bilo majčinog ili očevog alela. U slučaju GNAS1 gena u normalnim okolnostima dešava se očev imprinting dela GNAS1 gena zaduženog za sintezu Alpha subjedinice na nivou proksimalnog tubula. Iz tih razloga nasleđivanje GNAS1 mutacije od oca neće dovesti do rezistencije PTH na nivou proksimalnog tubula ali genski imprinting je tkivno specifičan i ne dešava se u svim tkivima zbog čega će se mutacija nasleđena od oca ispoljiti u drugim tkivima čime se može objasniti nastanak AHO (3). AHO obuhvata skup razvojnih i skeletnih poremećaja: brahimetakarpalija, brahimetatarzalija, nizak rast, zdepast izgled, gojaznost, okruglo lice, dentalna hipoplazija, kalcifikacije mekog tkiva i raličit stepen intelektualnog deficita. Brahidaktilija je najvažniji znak AHO. Nekoliko drugih skeletnih deformiteta su opisani kod pacijenata sa AHO: kratka ulna, iskrivljen radijus, deformiteti lakta, cubitus valgus, coxa vara, coxa valga, genu varum i genu valgum (4). Kliničke karakteristike PPHP se mogu uočiti u nekim porodicama gde nema PHP Ia. U ovim slučajevima dijagnoza PPHP je diskutabilna zato što su neke karakteristike AHO nespecifične i prisutne su u drugim poremećajima. AHO like sindrom predstavlja entitet koji se karakteriše pre svega brahidaktilijom i mentalnom retardacijom zbog čega se još naziva i brahidaktilija-mentalna retardacija sindrom (BDMR) (5). Ovi pacijenti sa AHO like fenotipom imaju normalnu funkciju alfa subjedinice stimulatornog G proteina. Ovaj sindrom nastaje kao posledica terminalne delecije na nivou hromozoma 2q37. U slučaju AHO like sindroma pored brahidaktilije i mentalne retardacije opisuju se i drugi poremećaji kao što su poremećaji ponašanja uključujući autizam, epi napadi, poremećaji spavanja, gojaznost, nizak rast, kraniofacijalni dismorfizam, srčani, gastro-intestinalni i genito-urinarni defekti. Do sada je opisano nešto više od 100 slučajeva sa 2q37 delecijom različite veličine. Većina ovih slučajeva se javlja kao de novo delecija i familijarni slučajevi su retki pre svega zbog toga što je mikrodelecija 2q37 povezana sa intelektualnim poremećajima mada su relativno skoro opisani i porodični slučajevi sa brahidaktilijom i niskim rastom ali bez intelektualnih poremećaja takođe sa 2q37.3 delecijom (6).
Zaključak Prikazana je pacijentkinja starosti 18 god. kod koje su registrovane fenotipske karakteristike AHO (brahidaktilija, nizak rast, intelektualni deficit, genu varum), ali bez rezistencije na delovanje PTH kao i drugih peptidnih hormona čije je delovanje vezano za alpha subjedinici stimulatornog G proteina. U porodičnoj anamnezi ujak
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ima kraći IV i V prst šaka, ali verovatno nema PHP Ia sobzirom da ne uzima nikakvu supstitucionu terapiju kalcijumom i vitaminom D. PPHP se uglavnom javlja u porodicama u kojima postoji PHP tip 1a i prenosi se od oca što nije slučaj kod naše pacijentkinje. Postoji teoretska mogućnost da je mutacija na nivou GNAS 1 gena kod pacijentkinje nastala de novo, ali isto tako bez genetskog ispitivanja ne može se sa sigurnošću isključiti ni delecija na nivou 2q37 hromozoma odnosno AHO like sindrom.
Reference: 1. Albright F, Burnett CH, Smith CH, Parson WW. Psudohypoparathyroidism: an example of Seabright Bantam syndrome. Endocrinology, 1942; 30: 922-932. 2. Michael A Levine. An update on the clinical and molecular characteristics of psudohypoparathyroidism. Curr Opin Endocrinol Diabetes Obes, 2012; 19(6): 443-451. 3. Merlin G Butler. Genomic imprinting disorders in humans: a mini review. J Assist Reprod Genet, 2009; 26: 477-486. 4. Giovanna Mantovani. Psudohypoparathyroidism: Diagnosis and Treatment. J Clin Endocrinol Metab, 2011; 96(10): 3020-3030. 5. Wilson LC, Leverton K, Luttikhuis O et al. Brachydactyly and Mental Retardation: An Albright Hereditary Osteodystrophy-like Syndrome Localized to 2q37. Am. J. Hum. Genet., 1995; 56: 400-407. 6. Jean-Marcais N¸ Decamp M, Ge´rard M et al. The First Familial Case of Inherited 2q37.3 Interstitial Deletion with Isolated Skeletal Abnormalities Including Brachydactyly Type E and Short Stature. Am J Med Genet, 2015; 167A:185–189.
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Danica Stamenković-Pejković1,2, Ana Gligić2, Goran Cvijović1,2, Svetlana Zorić2, Danka Jeremić A2, Snežana Polovina2, Aleksandra Kendereški1,2, Dragan Micić1, Mirjana Šumarac-Dumanović1,2
PSEUDOPSEUDOHYPOPARATHYROIDISM OR ALBRIGHT HEREDITARY OSTEODISTROPHY LIKE SYNDROME 1
Summary Introduction: pseudohypoparathyroidism (PHP) is hormone resistance syndrome described for the first time in 1942 by Albright et al. All this patients had high levels of the PTH and specific skeletal deformities which were later termed as Albright hereditary osteodystrophy (AHO). The PTH requires the alpha subunit of G protein for its action. GNAS1 gene encodes the alpha subunit of the G protein and molecular defects in this gene lead to the occurrance of at least four different forms of this syndrome. Pseudopseudohypoparathyroidism (PPHP) is a form of PHP which is characterized by physical features of AHO without any evidance of PTH resistance. Albright hereditary osteodystrophy like syndrome (AHO like syndrome) has some common characteristics with AHO but is not connected with the molecular defect in the GNAS 1 gene. Case outline: we repoported the case of the female patient with the phenotypic characteristics of AHO (brachydactyly, short stature, mild degree of intelectual deficit and genu varum) but without any evidance of PTH resistance. PPHP occurs mainly in families with PHP 1a and it is inherited from the father which is not the case with our patient. There is a theoretical possibility that the mutation of the GNAS 1 gene occurred de novo but without genetic testing the 2q37 deletion and AHO like syndrome can not be excluded. School of Medicine, Universisty of Belgrade.
1
Clinic for Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, Belgrade. 2
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Conclusion: in same cases of PPHP the diagnosis of AHO like syndrome should be considered but the only way to make the precise diagnosis is the genetic testing as it was in our case.
Key words: pseudopseudohypoparathyroidism, Albright hereditary osteodystrophy, Albright hereditary osteodystrophy like syndrome, GNAS 1 gene
Case report The eighteen years old female patient was admitted to the hospital under the suspicious of pseudopseudohypoparathyroidism due to additional endocrinological investigation. The patient was the first child from the normal pregnancy. She was born with the normal weight. Postnatal development was regular but from the birth the shortening of the fourth and fifth fingers of the left and right hand was noticed as well as deformed and shorter fourth finger of the right foot. She has bow legs from early childhood. She said she was the lowest in her class. Mother and father have a normal hight. Due to the problems with learning she left the school in the fifth grade. The first period was when she was 11 years old. Menstrual cycles are regular on every 30 days. She said she had the normal development of the secondary sexual characteristics. Since she was ten years old she had very often dislocation of the knees and that was the reason of the hospitalization in the orthopedic clinic. During that hospitlisation the hormonal analyses were done for the first time and the levels of TSH, PTH and serum calcium were in the normal range. Bone mineral density was measered by densitometry and showed significant decrease of the bone density (Z score of the femoral neck -2.8 and Z score of the lumbar spine L1-L4 -3.3). Before the decision on how to treat the dislocation of the knees the patient was admitted to our hospital for the additional examination. In addition to the above she denied other chronic diseases. In the family history the father and younger sister olso have bow legs (O legs), mather and older sister have the problems with knee dislocation, uncle has a shorter fourth and fifth fingers of the left and right hand. As far as she knows no one in her familiy has problem with low level of the calcium in the blood. Physical examination showed short stature (under 3d percentil) and lower BMI 18.9 kg/m2. During the conversation the patient gave the impression of mild intellectual deficit. Shortening of the fourth and fifth fingers of both hands was observed as well as shortened and deformed fourth finger of the right foot (Fig. 1 and Fig. 2.). The patient had a pronounced degree of genu varum and the rest of the physical examination was normal (Fig. 3). The results of routine laboratory tests were within the normal ranges including calcium, magnesium and phosphate levels in the serum as well as the value of the 24h urine calcium excretion. The endocrine examination showed the normal values of PTH,
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Fig. 1
Fig. 2
Fig. 3
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FT4, TSH, calcitonin, growth hormone, FSH, LH, estradiol, testosterone, SHBG, and DHEAS. The growth hormone response during the insulin tolerance test was normal. The concentration of vitamin D was low. The karyotype was normal (46 XX). First radiography showed reduction of fourth and fifth metacarpal bones on both hands (Fig. 4). Foot radiography showed reduction of fourth metatarsal bone of the right foot as well as reduction of the fourth proximal, intermediate and distal phalanx of the right foot (Fig. 5). The ultrasounds of the abdomen, pelvis and tyroid gland were normal.
Slika 4
Slika 5
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Discussion Pseudohypoparathyroidism (PHP) is historically the first hormone resistance syndrome and it was described for the first time in 1942 by Albright et al. (1). The term now encompasses a heterogeneous group of rare metabolic disorders, all characterized by end-organ resistance to the action of PTH (2). Albright reported patients with normal renal function in whom hypocalcemia and hyperphosphatemia were associated with a reduced calcemic and phosphaturic response to injected bovine parathyroid extract or the resistance on the PTH action. All this patients had high levels of the PTH and specific skeletal deformities which were later termed as Albright hereditary osteodystrophy (AHO) (1). The PTH receptor requires the heterotrimeric G protein as an intermediary coupling protein to stimulate adenylyl cyclase. The molecular defects in the GNAS1 gene which encodes the alpha subunit of the heterotrimeric G protein lead to the occurrance of at least four different forms of this syndrome: PHP Ia, PHP Ib, PHP Ic and pseudopseudohypoparathyroidism (PPHP) (Table 1.). In addition to PTH resistance some forms od PHP can show the resistance to the ather hormones which olso act trough the alpha subunit of the heterotrimeric G protein such as TSH, ADH, FSH, LH, glucagon, ACTH and GHRH (2). Tablela 1. Clasification of PHP
PHP I a
AHO
Hormone resistance
Heterotopic ossification
Yes
PTH, TSH, Gn, GHRH
Yes, superficial
PTH infusion ↓cAMP ↓phosphaturia
GNAS defect Maternal inactivating mutations Paternal inactivating mutations
PPHP
Yes
No
Yes, superficial
PHP I b
No
PTH, TSH
No
↓cAMP ↓phosphaturia
Impriting dysregulation
Yes
PTH, TSH, Gn
Yes, superficial
↓cAMP ↓phosphaturia
Few inactivating mutations
PHP Ic
Gn-gonadotropini;
Normal
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One form of PHP as noted in the table 1 is PPHP. Interestingly, patients showing the physical features of AHO without any evidance of PTH resistance were olso described by Albright et al. 10 years after their first report of PHP. This new syndrome which was termed PPHP may be preasnt either in kindreds in which PHP is present or as an isolated defect. The presence of physical features of AHO without PTH resistance are the main features of PPHP. The studies have shown that a mutation in GNAS1 gene in the same family if it is inherited from the mother leads to PHP 1a but if it is inherited from the father leads to PPHP. Alpha subunit of the G protein is synthesized in most cells thanks to the presence of both allels (father‘s and mother’s), however in some cells such as cells of the proximal renal tubules, somatotropic cells, thyrocytes, gonadal cells alpha sibunit is primarily synthesized due to the mother‘s allel. The fenomen of genetic imprinting involves the selective inactivation of mother’s or father’s alleles. In normal circumstances, there is the imprinting of the part of the GNAS 1 gene responsible for the synthesis of the alpha subunit in the proximal renal tubules. For these reasons inheritance of the GNAS 1 mutation from the father is not associated with the PTH resistance on the level of the proximal tubules. Imprinting is tissue selective and does not occur in all tissues and that is the explanation why the mutation inherited from the father occur in other tissues which may explain the occurrence of the AHO (3). AHO is a clinical entity which encompasses heterogeneous clinical findings such as brachydactyly, rounded face, short stature, central obesity, subcutaneous ossifications, and variable degrees of mental retardation. In particular, brachydactyly, classically described as a shortening of III, IV, and V metacarpals and I distal phalanx, is the typical and, together with heterotopic ossifications, the most specific feature of the AHO phenotype. However, in a major subset of patients, the diagnosis may remain unclear because occasional shortening of hand bones may sometimes be detected as a nonspecific finding in the normal population. Several other skeletal deformities have been described in AHO, including short ulna, bowed radius, deformed elbow, or cubitus valgus and coxa vara, coxa valga, genu varum, and genu valgum deformities (4). Clinical features of PPHP can be seen in some families where there is no PHP 1a. In these cases the diagnosis of PPHP is questionable because some of the features of AHO are nonspecific and can be seen in other disorders. Albright hereditary osteodystrophy like syndrome (AHO like syndrome) is also known as brachydactylymental retardation syndrome (5). This disorder includes intellectual disability, behavioral abnormalities including autism spectrum disorder, seizures, sleep disturbances, obesity, short stature, brachydactyly, craniofacial dysmorphism and cardiac, tracheal, gastrointestinal, and genito-urinary tract defects. The patients with AHO like syndrome have the normal function of the alpha subunit of the G protein. To date, about 100 patients have been reported with 2q37 deletion of different sizes. Most deletions are terminal and occur de novo. Familial cases are exceptional as microdeletion of 2q37 is associated with intellectual disability (6).
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Conclusion In conclusion we repoported the case of the female patient with the phenotypic characteristics of AHO (brachydactyly, short stature, mild degree of intelectual deficit and genu varum) but without any evidance of PTH resistance as well as other peptide hormones that act via alpha subunit of the stimulatory G protein. In the famyliy hystory the uncle has a shorter fourth and fifth fingers of the left and right hand but probablly does not have PHP Ia since he does not take any substitution therapy with calcium and vitamin D. PPHP occurs mainly in families with PHP 1a and it is inherited from the father which is not the case with our patient. There is a theoretical possibility that the mutation of the GNAS 1 gene occurred de novo but without genetic testing the 2q37 deletion and AHO like syndrome can not be excluded. Reference: 1. 2. 3. 4. 5.
Michael A Levine. An update on the clinical and molecular characteristics of psudohypoparathyroidism. Curr Opin Endocrinol Diabetes Obes, 2012; 19(6): 443-451. Merlin G Butler. Genomic imprinting disorders in humans: a mini review. J Assist Reprod Genet, 2009; 26: 477-486. Giovanna Mantovani. Psudohypoparathyroidism: Diagnosis and Treatment. J Clin Endocrinol Metab, 2011; 96(10): 3020-3030. Wilson LC, Leverton K, Luttikhuis O et al. Brachydactyly and Mental Retardation: An Albright Hereditary Osteodystrophy-like Syndrome Localized to 2q37. Am. J. Hum. Genet., 1995; 56: 400-407. Jean-Marcais N¸ Decamp M, Ge´rard M et al. The First Familial Case of Inherited 2q37.3 Interstitial Deletion with Isolated Skeletal Abnormalities Including Brachydactyly Type E and Short Stature. Am J Med Genet, 2015; 167A:185–189.