Genetic Endocrine Disorders

• Genetic disorders can affect the endocrine system, with a variety of presentations, inheritance patterns, and genetic causes

Learning Objectives

• Modes of inheritance, including autosomal dominant, autosomal recessive, and X-linked, can be identified using family history or pedigree information
• Common genetic causes of endocrine disorders can be reviewed
• The genetic causes of congenital hypothyroidism correlate with thyroid hormone synthesis
• Modes of inheritance for congenital nephrogenic diabetes insipidus (NDI) and central diabetes insipidus (CDI) can be identified
• The role of genetic testing can be distinguished in congenital adrenal hyperplasia
• The mechanism of inheritance is correlated for diffuse and focal congenital hyperinsulinism
• The mode of inheritance and genetic testing associated with MEN1 can be identified
• Consequences of genetic defects can be differentiated in GH or IGF-1 deficiency

Topics Covered

• Presentation relates to requiredElement 3.1, foundational Biomedical Sciences Knowledge Base, Community Health and Patient Presentations related to wellness, Endocrine system and Metabolism, and Laboratory Test Findings and diagnostic imaging
• Presentation related to human development and genetics, pituitary disorders, multiple endocrine neoplasia (MEN1, MEN2), and congenital disorders
• Genetic conditions for review include congenital hypothyroidism, diabetes insipidus, congenital adrenal hyperplasia, congenital hyperinsulinism (diffuse and focal), multiple endocrine neoplasia, and short stature from growth hormone or IGF-1 defects

Congenital Hypothyroidism (CH)

• Gland dysgenesis causes ~ 80% of gland dysgenesis
• Primary CH is caused by a smaller organ developmental defect that can be sporadic
• CH can also result from genetic defects in thyroid hormone synthesis (thyroid dyshormogenesis)
• Reduced negative feedback to the AP results in increased TSH
• Patients can have enlarged thyroid if untreated (goiter)
• Newborn screening is done for hypothyroidism that can be primary or cause a clinical suspicion, elevated TSH indicates primary CH
• TSH can be normal/low, and elevated T4 indicates secondary CH

CH - Defective Hormone Synthesis

• Some genes identified in primary CH thyroid dysgenesis are mostly sporadic
• AP defect can result in central CH with the corresponding TSH level being abnormal
• Autosomal recessive inheritance requires newborn screening and genetic testing
• Expect low T4 and T3 with normal TSH (bioactivity will be low)
• Treatment is started once a diagnosis is made w/o the need for genetic testing
• Thyroid dysgenesis: TTF2, PAX8, NKX2--1
• Thyroid Hormonogenesis: SLC5A5, SLC26A4, TG, TPO, DUOX2

Diabetes Insipidus

• The condition has multiple types
• The central type is caused by decreased release of ADH or response to it, and nephrogenic types can also cause reduced release
• Also results from complications during pregnancy
• Common symptoms consist of polyuria, polydipsia, and chronic dehydration
• Water deprivation and desmopressin are used to differentiate between types
• In nephrogenic – there is a lack of ability to concentrate urine accompanied by no response to desmopressin

Genetics of Diabetes Insipidus (DI)

• The majority of central DI cases have idiopathic origins
• Mutations in the ADH gene can cause mutations
• DI is an autosomal dominant inheritance condition
• Nephrogenic DI is caused by an insensitivity to AVP
• Two genes control nephrogenic DI with multiple allelotypes
• Mutations in AVPR2, which is X-linked cause DI, in approximately 90% of cases
• Other 10% result from AQP2 mutations, which are autosomal recessive/ autosomal dominant
• DI typically presents at birth Genetic testing varies if the disease is FNDI, or NDI

Congenital Hyperinsulinism (HI)

• Non-genetic perinatal stress leading to HI occurs in preeclampsia
• Congenital HI is caused by mutations in the insulin secretion pathway
• SUR1, Kir6.2 mutations in KATP channel are the most common
• Autosomal Recessive is the general mode of inheritance for the disease
• Insulin secretion remains constant ("on" signal) with no regulation by glucose

Diffuse vs. Focal HI

• The conditions present in two histological forms, diffuse and focal
• Biallelic recessive mutations such as ABCC8 > KCNJ11 cause Diffuse HI, where all pancreatic β-cells are affected
• Focal HI has hyperplastic islet lesion or focal adenomatosis, with the "2-hit hypothesis" featuring in this condition
• HI has an inherited paternal mutation – hit 1, in addition to the somatic maternal loss of allele – hit 2

Characteristics of Congenital HI

• Hyperinsulinism results in hypoglycemia with hypoglycemia diagnosis in children is not standardized but elevated insulin levels should be seen
• Diffuse and focal HI will present similarly
• Diffuse presents earlier with babies being on average heavier and larger in size
• Focal commonly presents with a seizure
• Both conditions have higher than normal insulin levels, although diffuse has a higher average than focal
• Hyperinsulinemiac hypoglycemia inheritance pattern indicates the mode of inheritance

Multiple Endocrine Neoplasia (MEN1)

• Rare, occurs in 2-3 per 100,000 people
• Diagnosis is based on 2 of 3 main endocrine tumors or 1 main tumor with a first-degree relative with MEN1
• Tumors consist parathyroid adenomas (90%), enteropancreatic endocrine tumors (60%), pituitary adenoma (40%)
• Additional tumors may develop in the stomach, thymus, and lung The parathyroid tumor results in hypercalcemia, with too much parathyroid hormone, also primary hyperparathyroidism as the first clinical sign
• Diagnosed using pitutary tumor type: MRI
• Mean life expectancy is 47 years but depends on the tumor type
• Most MEN1 is inherited (90%), de novo mutation occurs only 10% of the time
• Mode of inheritance is autosomal dominant

Short Stature

• Many reasons are known for short stature
• Short statures often depends on uterine growth conditions, childhood environment, with major genetic components
• Definition according to the FDA is less than >2.25 SD for age
• If accompanied by dysmorphic features karyotype should be obtained to rule out chromosomal anomalies
• Karyotype is required in females with short stature to rule out Turner even without signs of classical presentation
• Numerous conditions are associated with skeletal disorders

GH/IGF-1 Axis Growth Failure

• GH has functions postnatally, causing the condition, and observe postnatal growth restriction
• IGF-1 functions both pre and postnatally, where mutations result in both, causing the in utero, and post birth growth restriction
• Genetic testing is not widely available and done on a case-by-case basis at the IGF Deficiency Research Center at Oregon Health & Science University in Portland, Oregon About 75% of isolated GHD is genetic etiology and not physical anomalies of the hypothalamus or pituitary
• IGHD type 1a: no GH is present. GH1 mutation
  • Severe.
  • Autosomal Recessive 1a type is characterized no GH in serum while 1b has some. IGHD type lb: Some GH response.
    • More mild
    • Autosomal Recessive

Laron Syndrome

• Mostly autosomal recessive, GHT mutations can cause the condition
• Severe short stature, midface hypoplasia
• Intellect and head development are both normal
• Causes the body to be unable to use growth hormone
• Results in hypoglycemia, delayed puberty, short limbs, obesity
• Some genes include SOX3, PITX2, Prop1, PouF1