scholarly journals An Uncommon Case of Hypophophatasia Presenting With Galactorrhea, Diagnosed at a Later Age Than Expected

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A180-A181
Author(s):  
Amelia Guzman Bicchi ◽  
Antonio Lubrano Heinsen ◽  
Marla Sevilla ◽  
John Tourtelot ◽  
Joaquin Gomez-Daspet
Keyword(s):  
Alkaline Phosphatase ◽  
Joint Pain ◽  
Genetic Disorder ◽  
Brain Mri ◽  
Treatment Modalities ◽  
White Female ◽  
Inorganic Pyrophosphate ◽  
Enzyme Replacement ◽  
History Of ◽  
Alkaline Phosphate

Abstract Hypophosphatasia is a rare genetic disorder which causes accumulation of inorganic pyrophosphate that in turn inhibits mineralization. It is caused by a mutation in the non-specific alkaline phosphatase gene (TNSALP). We will review the diagnosis during adulthood when the presentation is characterized by poor healing, recurrent metatarsal stress fractures and bone pain. We are reporting the case of a 38-year-old white female with history of Melanoma referred to the Pituitary Clinic due to galactorrhea. During the encounter it was noted that she had history of disseminated joint pain, myalgias, periodontal complications as well as biochemical evidence of low alkaline phosphatase. At age three she had premature teeth loss, and clumsy gait, which later resolved. She was evaluated for this and diagnosed with odontohypophophatasia at which time no treatment was initiated. As an adult patient had two non-traumatic ankle fractures with associated frail teeth, chipping, and cracking without significant trauma. At around 36 years of age, patient started developing worsening joint pain, stiffness, myalgias and 35 pounds weight gain. Family History is remarkable for her father, having history of low alkaline phosphate and odontogenic infections with no joint or muscle pain. Paternal grandmother had history of dental infections and frail teeth. The patient has four sons; her oldest son has low alkaline phosphate with no clinical symptoms. Patient’s biochemical analysis was unremarkable except for low alkaline phosphate range between 25–38 U/L (40–125 U/L) and elevated Vitamin B6 69.5 ng/mL (2.1–21.7 ng/mL). The physical exam was unremarkable. Brain MRI showed a 3 mm microadenoma with normal pituitary hormonal workup, including diluted prolactin. Mammogram did not show any abnormalities. It was determined that the pituitary microadenoma was non-functioning, and galactorrhea was not hormonal mediated. The patient was referred to a genetic specialist for evaluation of Hypophosphatasia. Testing for TNSALP mutation was done which showed an ALP Mutation variant c.1172G>A (p. Arg391His). She was started on asfotase alfa (Strensiq) an enzyme replacement for Hypophosphatasia, in November 2019. Hypophosphatasia is a rare condition often diagnosed during early life. Due to wide number of possible mutations in the TNSALP gene, the clinical presentation can vary between patients and diagnosis can be elusive. In our patient, despite being diagnosed with odontohypophophatasia at an early age, and having many periodontal complications, hypophosphatasia was not confirmed until more than 30 years after the initiation of symptoms. In the management of Hypophosphatasia, having an accurate timely diagnosis can provide patients with early intervention of advanced treatment modalities such as Strensiq that can improve symptoms.

scholarly journals Hypophosphatasia: A Unique Disorder of Bone Mineralization

2021 ◽  
Vol 22 (9) ◽  
pp. 4303
Author(s):  
Juan Miguel Villa-Suárez ◽  
Cristina García-Fontana ◽  
Francisco Andújar-Vera ◽  
Sheila González-Salvatierra ◽  
Tomás de Haro-Muñoz ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Genetic Disease ◽  
Therapeutic Strategy ◽  
Pediatric Patients ◽  
Bone Mineralization ◽  
Clinical Manifestations ◽  
Allelic Heterogeneity ◽  
Specific Enzyme ◽  
Inorganic Pyrophosphate ◽  
Enzyme Replacement

Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5′-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.

Screening for hypophosphatasia: does biochemistry lead the way?

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Corinna Melanie Held ◽  
Anic Guebelin ◽  
Andreas Krebs ◽  
Jörn Oliver Sass ◽  
Michael Wurm ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Enzyme Replacement Therapy ◽  
Pediatric Population ◽  
Laboratory Data ◽  
Diagnostic Algorithm ◽  
Inorganic Pyrophosphate ◽  
Enzyme Replacement ◽  
Underlying Diseases ◽  
Data Screening ◽  
Serum And Urine

Abstract Objectives Patients with childhood hypophosphatasia (HPP) often have unspecific symptoms. It was our aim to identify patients with mild forms of HPP by laboratory data screening for decreased alkaline phosphatase (AP) within a pediatric population. Methods We conducted a retrospective hospital-based data screening for AP activity below the following limits: Girls: ≤12 years: <125 U/L; >12 years: <50 U/L Boys: ≤14 years: <125 U/L; >14 years: <70 U/L. Screening positive patients with otherwise unexplained hypophosphatasemia were invited for further diagnostics: Re-test of AP activity, pyridoxal 5′-phosphate (PLP) in hemolyzed whole blood, phosphoethanolamine (PEA) in serum and urine, and inorganic pyrophosphate in urine. Sequencing of the ALPL gene was performed in patients with clinical and/or laboratory abnormalities suspicious for HPP. Results We assessed a total of 14,913 samples of 6,731 patients and identified 393 screening-positive patients. The majority of patients were excluded due to known underlying diseases causing AP depression. Of the 30 patients who participated in the study, three had a decrease in AP activity in combination with an increase in PLP and PEA. A heterozygous ALPL mutation was detected in each of them: One patient with a short stature was diagnosed with childhood-HPP and started with enzyme replacement therapy. The remaining two are considered as mutation carriers without osseous manifestation of the disease. Conclusions A diagnostic algorithm based on decreased AP is able to identify patients with ALPL mutation after exclusion of the differential diagnoses of hypophosphatasemia and with additional evidence of increased AP substrates.

scholarly journals Hypophosphatasia

2021 ◽  
Vol 10 (23) ◽  
pp. 5676
Author(s):  
Symeon Tournis ◽  
Maria P. Yavropoulou ◽  
Stergios A. Polyzos ◽  
Artemis Doulgeraki
Keyword(s):  
Alkaline Phosphatase ◽  
Autosomal Dominant ◽  
Serum Alkaline Phosphatase ◽  
Severe Disease ◽  
Loss Of Function ◽  
Inorganic Pyrophosphate ◽  
Live Births ◽  
Enzyme Replacement ◽  
Asfotase Alfa ◽  
Reduced Activity

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5΄-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.

scholarly journals Hypophosphatasia Misdiagnosed as Osteoporosis in a Young Girl

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A201-A202
Author(s):  
Tiffany Tsang ◽  
Maya P Raghuwanshi
Keyword(s):  
Alkaline Phosphatase ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Muscular Atrophy ◽  
Mineral Metabolism ◽  
Pulmonary Complications ◽  
Inherited Disease ◽  
Inorganic Pyrophosphate ◽  
Enzyme Replacement ◽  
Asfotase Alfa

Abstract Introduction: Hypophosphatasia (HPP) is a rare inherited disease of mineral metabolism characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNALP), which causes an inability to liberate inorganic phosphate for hydroxyapatite crystal propagation as well as toxic accumulation of inorganic pyrophosphate, pyridoxal-5’-phosphate and urinary phosphoethanolamine. It has a prevalence of 1/100,000 to 1/900,000, although milder forms have an estimated prevalence of 1/6,370. Variable mutations in TNALP cause clinical expressions ranging from a severe perinatal form, which is often fatal after birth from pulmonary complications, to an infantile form, which can cause vitamin B6-responsive seizures, to an asymptomatic adult form. Case: A 27-year-old, ventilator-dependent female with osteoporosis, hypothyroidism, cerebral palsy with previous spinal fusion, seizure disorder and nephrocalcinosis presented with surgical site infection from a right femur ORIF she underwent a month ago. She had a history of microfractures and low-impact fractures of both femurs requiring several surgeries. Osteoporosis was diagnosed at age 5 and she had been on Fosamax ever since. She did not meet any developmental milestones as a baby and never reached menarche. Various diagnoses by multiple specialists did not fully explain her clinical presentation. Her medications included alendronate 5 mg, calcium carbonate 600 mg, ergocalciferol 400 U and levothyroxine 50 mcg. Physical exam showed poor dentition, a misshapen skull and bowed legs with contractures of her extremities. Her labs revealed Ca 9.1 mg/dL (8.4–10.2 mg/dL), albumin 3.2 gm/dL (3.5–5.2 gm/dL), phosphorus 5.1 mg/dL (2.5–4.5 mg/dL), alkaline phosphatase 32 U/L (35–105 U/L), PTH 28 pg/mL (15–65 pg/mL), vitamin D 33.5 ng/mL (30–100 ng/mL), C-telopeptide 509 pg/mL (34–635 pg/mL). A right knee X-Ray reported diffusely gracile and demineralized bones with muscular atrophy. She recently transitioned care from a pediatric endocrinologist to an adult endocrinologist, who tested her positive for heterozygous ALPL pathogenic variant hypophosphatasia and was considering her for asfotase alfa enzyme replacement therapy. Discussion: Our patient had infantile HPP, but due to misdiagnosis as osteoporosis, she was inappropriately treated with a bisphosphate for over 20 years. Treatment of HPP had been supportive until the approval of asfotase alfa (Strensiq) in October 2015. It is a bone-targeted human recombinant enzyme replacement therapy approved for infantile- and juvenile-onset HPP and has been shown to decrease mortality from 73% to 16% at age 5. With improvement in life-sustaining technology, more HPP patients are able to survive into adulthood. Awareness of the complex and polymorphic presentation of HPP by adult endocrinologists is paramount for accurate diagnosis, thus avoiding inappropriate treatments.

Z-line degradation and phagocytosis of sarcomeric fragments in myonecrosis

1983 ◽  
Vol 41 ◽  
pp. 790-791
Author(s):  
Melinda L. Estes ◽  
Samuel M. Chou
Keyword(s):  
Vastus Lateralis ◽  
Inflammatory Myopathy ◽  
Muscle Disease ◽  
White Female ◽  
Inflammatory Cell Infiltrate ◽  
Limb Weakness ◽  
Muscle Diseases ◽  
History Of ◽  
The Right ◽  
Mononuclear Inflammatory Cell

Many muscle diseases show common pathological features although their etiology is different. In primary muscle diseases a characteristic finding is myofiber necrosis. The mechanism of myonecrosis is unknown. Polymyositis is a primary muscle disease characterized by acute and subacute degeneration as well as regeneration of muscle fibers coupled with an inflammatory infiltrate. We present a case of polymyositis with unusual ultrastructural features indicative of the basic pathogenetic process involved in myonecrosis.The patient is a 63-year-old white female with a one history of proximal limb weakness, weight loss and fatigue. Examination revealed mild proximal weakness and diminished deep tendon reflexes. Her creatine kinase was 1800 mU/ml (normal < 140 mU/ml) and electromyography was consistent with an inflammatory myopathy which was verified by light microscopy on biopsy muscle. Ultrastructural study of necrotizing myofiber, from the right vastus lateralis, showed: (1) degradation of the Z-lines with preservation of the adjacent Abands including M-lines and H-bands, (Fig. 1), (2) fracture of the sarcomeres at the I-bands with disappearance of the Z-lines, (Fig. 2), (3) fragmented sarcomeres without I-bands, engulfed by invading phagocytes, (Fig. 3, a & b ), and (4) mononuclear inflammatory cell infiltrate in the endomysium.

845 Progressive external ophthalmoplegia in sleep apnea presenting as floppy eyelid syndrome

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A329-A329
Author(s):  
Pratibha Anne ◽  
Rupa Koothirezhi ◽  
Ugorji Okorie ◽  
Minh Tam Ho ◽  
Brittany Monceaux ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Surgical Treatment ◽  
Sleep Apnea ◽  
Genetic Disorder ◽  
Deltoid Muscle ◽  
Progressive External Ophthalmoplegia ◽  
Ataxic Gait ◽  
Pressure Setting ◽  
Obstructive Sleep ◽  
History Of

Abstract Introduction Floppy eye lid syndrome (FES) is known to be associated with Obstructive sleep apnea (OSA) and chronic progressive external ophthalmoplegia (CPEO) is a rare genetic disorder with mitochondrial myopathy that may present with isolated eye lid ptosis in the initial stages. In a patient with loud snoring and obesity, treating obstructive sleep apnea may improve Floppy eyelid syndrome. Report of case(s) 52-year-old African – American male with past medical history of Hypertension, obesity, glaucoma, CPEO status bilateral blepharoplasty with failed surgical treatment. Patient was referred to Sleep medicine team to rule out Obstructive Sleep Apnea aa a cause of possible underlying FES and residual ptosis. On exam, patient was noted to have bilateral brow and eyelid ptosis and mild ataxic gait. MRI brain with and without contrast was unremarkable. Deltoid muscle biopsy was suggestive of possible congenital myopathy and mild denervation atrophy. Polysomnogram showed severe OSA with AHI of 74.1 per hour and patient was initiated on Auto CPAP at a pressure setting of 7–20 cm H2O. CPAP treatment improved snoring, OSA and subjective symptoms of excessive day time sleepiness but did not improve the residual ptosis. Conclusion Treatment of severe OSA in a patient previously diagnosed with CPEO and failed surgical treatment with bilateral blepharoplasty, did not alter the course of residual ptosis/ floppy eyelids even though his other sleep apnea symptoms have improved. Support (if any) 1. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. Ophthalmic Plast Reconstr Surg. 1997 Jun;13(2):98–114. doi: 10.1097/00002341-199706000-00005. PMID: 9185193.

scholarly journals A Case Report of a Prenatally Missed Mowat-Wilson Syndrome With Isolated Corpus Callosum Agenesis

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110065
Author(s):  
Nesrin Şenbil ◽  
Zeynep Arslan ◽  
Derya Beyza Sayın Kocakap ◽  
Yasemin Bilgili
Keyword(s):  
Corpus Callosum ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Gene Mutations ◽  
Hirschsprung Disease ◽  
Agenesis Of Corpus Callosum ◽  
Whole Exome ◽  
Congenital Cardiac Anomalies ◽  
History Of ◽  
Gene Mutation Analysis

Mowat–Wilson syndrome (MWS) is an autosomal dominant genetic disorder caused by ZEB2 gene mutations, manifesting with unique facial characteristics, moderate to severe intellectual problems, and congenital malformations as Hirschsprung disease, genital and ophthalmological anomalies, and congenital cardiac anomalies. Herein, a case of 1-year-old boy with isolated agenesis of corpus callosum (IACC) in the prenatal period is presented. He was admitted postnatally with Hirschsprung disease (HSCR), hypertelorism, uplifted earlobes, deeply set eyes, frontal bossing, oval-shaped nasal tip, ‘‘M’’ shaped upper lip, opened mouth and prominent chin, and developmental delay. Hence, MWS was primarily considered and confirmed by the ZEB2 gene mutation analysis. His karyotype was normal. He had a history of having a prenatally terminated brother with similar features. Antenatally detected IACC should prompt a detailed investigation including karyotype and microarray; even if they are normal then whole exome sequencing (WES) should be done.

scholarly journals A215 MDR3 DEFICIENCY MIMICKING WILSON DISEASE

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 247-248
Author(s):  
M Flanagan ◽  
R Little ◽  
I Siddiqui ◽  
N Jones ◽  
V Ng
Keyword(s):  
Bile Acids ◽  
Wilson Disease ◽  
Genetic Disorder ◽  
Multi Drug Resistance ◽  
Total Serum ◽  
Cholestatic Liver Disease ◽  
Class Iii ◽  
Her Family ◽  
Abcb4 Gene ◽  
History Of

Abstract Background The chronic phenotype of ALF includes a broad differential diagnosis. Class III multi-drug resistance P-glycoprotein 3 (MDR3) deficiency, also referred to as progressive familial intrahepatic cholestasis type 3, is an autosomal recessive genetic disorder. It is caused by a defect on the ABCB4 gene located on chromosome 7, which encodes MDR3. MDR3 is responsible for transporting phosphatidylcholine across the canalicular membrane, thereby allowing it to be incorporated into bile micelles. MDR3 deficiency results in increased levels of free bile acids and detergent bile. Progressive cholangiopathy ensues from this detergent bile and indirectly leads to cholestasis and liver failure in severe cases. Significantly increased urinary and hepatic copper (Cu), which are hallmarks of Wilson disease, have also been reported in patients with acute hepatitis and cholestasis including patients with MDR3 deficiency Aims We report a case of a girl who presented with a chronic phenotype of PALF, who had multiple features of Wilson disease and so was treated as such until genetic analysis confirmed MDR3 deficiency Methods Results A 6 year old girl presented to the ED with a 1mth history of epistaxis and a 1wk history of abdominal pain and distension, facial edema, pallor and fever. Her family history was significant for parental consanguinity and maternal itch during pregnancy. On examination she had clubbing, scleral icterus and a distended abdomen with hepatosplenomegaly. Her bloodwork showed bicytopenia (HGB 53 & Plts 63) along with liver dysfunction (INR 2.9, albumin 25, conjugated bilirubin 9) and raised liver enzymes (transaminases & GGT &gt;10xULN). Her total serum bile acids were raised at 134. An US showed hepatosplenomegaly with multiple hyperechoic nodules and perisplenic varices. She was extensively worked up for malignancy, autoimmune and metabolic disease. Serum ceruloplasmin was reduced, ophthalmology examination showed no KF rings and her 24hr urinary Cu was 10xULN. Liver Cu quantification was markedly raised at 40xULN. Liver biopsy showed cirrhosis with fibrosis related minimal non-specific portal and septal inflammation. Additionally, complete loss of canalicular staining on immunohistochemistry for MDR3 protein was noted, suggestive of MDR3 deficiency. Based on the Cu levels, a provisional diagnosis of Wilson disease was made and Cu chelation therapy was commenced pending genetic testing. A cholestatic gene panel subsequently showed homozygous pathogenic variant for the ABCB4 gene. Trientine was stopped and she was commenced on ursodeoxycholic acid. Though biochemically she remains largely unchanged, she is clinically stable whilst awaiting a liver transplant Conclusions This case highlights the diagnostic difficulties associated with Cu test result interpretation in patients with chronic cholestatic liver disease and urges a thorough consideration of alternative diagnoses of PALF Funding Agencies None

scholarly journals Hereditary haemorrhagic telangiectasia: A case report

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110030
Author(s):  
Asfandyar Mufti ◽  
Muskaan Sachdeva ◽  
Khalad Maliyar ◽  
Marissa Joseph
Keyword(s):  
Arteriovenous Malformations ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Lower Lip ◽  
Recurrent Epistaxis ◽  
Receptor Like Kinase ◽  
History Of ◽  
The Right ◽  
Symptoms And Signs

Background: Hereditary haemorrhagic telangiectasia is an autosomal dominant genetic disorder characterized by abnormalities in blood vessel formation. The clinical manifestations of patients affected with hereditary haemorrhagic telangiectasia include mucocutaneous telangiectasias and visceral arteriovenous malformations. Case Summary: We report the case of a 30-year-old female diagnosed with hereditary haemorrhagic telangiectasia presenting with the classic triad of recurrent epistaxis, mucocutaneous telangiectasias and family history of hereditary haemorrhagic telangiectasia with activin receptor-like kinase 1 mutation. Upon skin examination, she was noted to have telangiectasias under left naris, inner lower lip and surface of the tongue, and a vascular malformation on the right forearm. Conclusion: Although the skin involvement and epistaxis may be mild symptoms and signs of hereditary haemorrhagic telangiectasia, timely recognition of these can ensure vigilant monitoring of potential severe complications from cerebral and pulmonary visceral arteriovenous malformations.

Intracranial meningioma in a patient with osteogenesis imperfecta

Open Medicine ◽  
2008 ◽  
Vol 3 (4) ◽  
pp. 517-520
Author(s):  
Parmenion Tsitsopoulos ◽  
Ioannis Anagnostopoulos ◽  
Vasileios Tsitouras ◽  
Ioannis Venizelos ◽  
Philippos Tsitsopoulos
Keyword(s):  
Osteogenesis Imperfecta ◽  
Muscle Power ◽  
Brain Mri ◽  
Intracranial Meningioma ◽  
Type I ◽  
Mri Scans ◽  
Heritable Disorder ◽  
History Of ◽  
One Year ◽  
Gait Disturbances

AbstractOsteogenesis imperfecta (OI) is a heritable disorder characterized mainly by connective tissue manifestations. In dinstinct cases, several neurological features have also been described. A 46-year-old male with a known family history of OI type I presented with progressive gait disturbances and diminished muscle strength. Brain MRI scans revealed an infiltrative intracranial mass occupying both frontoparietal lobes. The patient underwent surgical intervention. The histological diagnosis was an atypical (Grade II) meningioma. The bony parts demonstrated a mixture of osseous defects due to OI and infiltration by the tumor. At one-year follow up the patient′s muscle power partially returned while repeat MRI scans were negative for tumor recurrence.

Sign in / Sign up

Export Citation Format

Share Document