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Neonatal diabetes mellitus with congenital hypothyroidism(NDH)

MedGen UID:
347541
Concept ID:
C1857775
Disease or Syndrome
Synonym: NDH SYNDROME
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): GLIS3 (9p24.2)
 
Monarch Initiative: MONDO:0012436
OMIM®: 610199
Orphanet: ORPHA79118

Definition

Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome is characterized by intrauterine growth retardation and onset of nonimmune diabetes mellitus within the first few weeks of life. Other features include renal parenchymal disease, primarily renal cystic dysplasia, and hepatic disease, with hepatitis in some patients and hepatic fibrosis and cirrhosis in others. Facial dysmorphism, when present, consistently involves low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Most patients exhibit developmental delay (Dimitri et al., 2015). [from OMIM]

Clinical features

From HPO
Polycystic kidney disease
MedGen UID:
9639
Concept ID:
C0022680
Disease or Syndrome
The presence of multiple cysts in both kidneys.
Renal cyst
MedGen UID:
854361
Concept ID:
C3887499
Disease or Syndrome
A fluid filled sac in the kidney.
Portal hypertension
MedGen UID:
9375
Concept ID:
C0020541
Disease or Syndrome
Increased pressure in the portal vein.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Cholestasis
MedGen UID:
925
Concept ID:
C0008370
Disease or Syndrome
Impairment of bile flow due to obstruction in bile ducts.
Hepatitis
MedGen UID:
5515
Concept ID:
C0019158
Disease or Syndrome
Inflammation of the liver.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Pancreatic cysts
MedGen UID:
45293
Concept ID:
C0030283
Disease or Syndrome
A cyst of the pancreas that possess a lining of mucous epithelium.
Hepatic fibrosis
MedGen UID:
116093
Concept ID:
C0239946
Disease or Syndrome
The presence of excessive fibrous connective tissue in the liver. Fibrosis is a reparative or reactive process.
Pancreatic hypoplasia
MedGen UID:
539808
Concept ID:
C0266267
Congenital Abnormality
Hypoplasia of the pancreas.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Sagittal craniosynostosis
MedGen UID:
140921
Concept ID:
C0432123
Congenital Abnormality
A kind of craniosynostosis affecting the sagittal suture.
Thoracolumbar scoliosis
MedGen UID:
196671
Concept ID:
C0749379
Anatomical Abnormality
Wide anterior fontanel
MedGen UID:
400926
Concept ID:
C1866134
Finding
Enlargement of the anterior fontanelle with respect to age-dependent norms.
Hiatus hernia
MedGen UID:
483347
Concept ID:
C3489393
Disease or Syndrome
The presence of a hernia in which the upper part of the stomach, i.e., mainly the gastric cardia protrudes through the diaphragmatic esophageal hiatus.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Splenic cyst
MedGen UID:
452367
Concept ID:
C0272407
Disease or Syndrome
A closed sac located in the spleen.
Anti-thyroid peroxidase antibody positivity
MedGen UID:
1392952
Concept ID:
C4476743
Laboratory or Test Result
The presence of autoantibodies (immunoglobulins) in the serum that react against thyroid peroxidase.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Increased circulating thyroglobulin concentration
MedGen UID:
1375023
Concept ID:
C4476805
Finding
An abnormal elevation of the concentration of thyroglobulin, a protein produced in the thyroid gland that acts as a precursor to thyrroid hormones.
Choanal atresia
MedGen UID:
3395
Concept ID:
C0008297
Congenital Abnormality
Absence or abnormal closure of the choana (the posterior nasal aperture). Most embryologists believe that posterior choanal atresia results from a failure of rupture between the 35th and 38th day of fetal life of the partition which separates the bucconasal or buccopharyngeal membranes. The resultant choanal atresia may be unilateral or bilateral, bony or membranous, complete or incomplete. In over 90 per cent of cases the obstruction is bony, while in the remainder it is membranous. The bony type of atresia is commonly located 1-2 mm. anterior to the posterior edge of the hard palate, and the osseous septum varies in thickness from 1 to 10 mm. In the membranous form of choanal atresia the obstruction usually occurs further posteriorly. In approximately one third of cases the atresia is bilateral.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Congenital hypothyroidism
MedGen UID:
41344
Concept ID:
C0010308
Disease or Syndrome
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.\n\nCongenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.\n\nSigns and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.\n\nCongenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Elevated circulating thyroid-stimulating hormone concentration
MedGen UID:
108325
Concept ID:
C0586553
Finding
Increased concentration of thyroid-stimulating hormone (TSH) in the blood circulation.
Decreased circulating T4 concentration
MedGen UID:
1611997
Concept ID:
C4531078
Finding
A reduction below the normal concentration of thyroxine in the blood. Thyroxine (also known as T4) is the main hormone secreted by the thyroid gland into the blood. It can be converted into the active form triiodothyronine (also known as T3).
Raised intraocular pressure
MedGen UID:
68606
Concept ID:
C0234708
Finding
Intraocular pressure that is 2 standard deviations above the population mean.
Glaucoma of childhood
MedGen UID:
453382
Concept ID:
C2981140
Disease or Syndrome
Structural abnormalities that impede fluid drainage in the eye increase ocular pressure. These abnormalities may be present at birth and usually become apparent during the first year of life. Such structural abnormalities may be part of a genetic disorder that affects many body systems, called a syndrome. If glaucoma appears before the age of 3 without other associated abnormalities, it is called primary congenital glaucoma.\n\nOther individuals experience early onset of primary open-angle glaucoma, the most common adult form of glaucoma. If primary open-angle glaucoma develops during childhood or early adulthood, it is called juvenile open-angle glaucoma.\n\nUsually glaucoma develops in older adults, in whom the risk of developing the disorder may be affected by a variety of medical conditions including high blood pressure (hypertension) and diabetes mellitus, as well as family history. The risk of early-onset glaucoma depends mainly on heredity.\n\nIn most people with glaucoma, the damage to the optic nerves is caused by increased pressure within the eyes (intraocular pressure). Intraocular pressure depends on a balance between fluid entering and leaving the eyes.\n\nGlaucoma is a group of eye disorders in which the optic nerves connecting the eyes and the brain are progressively damaged. This damage can lead to reduction in side (peripheral) vision and eventual blindness. Other signs and symptoms may include bulging eyes, excessive tearing, and abnormal sensitivity to light (photophobia). The term "early-onset glaucoma" may be used when the disorder appears before the age of 40.
Buphthalmos
MedGen UID:
1641795
Concept ID:
C4551507
Congenital Abnormality
Diffusely large eye (with megalocornea) associated with glaucoma.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVNeonatal diabetes mellitus with congenital hypothyroidism
Follow this link to review classifications for Neonatal diabetes mellitus with congenital hypothyroidism in Orphanet.

Professional guidelines

PubMed

Yap PPH, Papachristou Nadal I, Rysinova V, Basri NI, Samsudin IN, Forbes A, Noor NM, Supian ZA, Hassan H, Paimin F, Zakaria R, Mohamed Alias SR, Ismail Bukhary NB, Benton M, Ismail K, Chew BH
BMJ Open 2022 Jul 26;12(7):e052554. doi: 10.1136/bmjopen-2021-052554. PMID: 35882454Free PMC Article

Recent clinical studies

Etiology

Hizkiyahu R, Badeghiesh A, Baghlaf H, Dahan MH
J Matern Fetal Neonatal Med 2023 Dec;36(2):2278027. Epub 2023 Nov 7 doi: 10.1080/14767058.2023.2278027. PMID: 37935517
Yap PPH, Papachristou Nadal I, Rysinova V, Basri NI, Samsudin IN, Forbes A, Noor NM, Supian ZA, Hassan H, Paimin F, Zakaria R, Mohamed Alias SR, Ismail Bukhary NB, Benton M, Ismail K, Chew BH
BMJ Open 2022 Jul 26;12(7):e052554. doi: 10.1136/bmjopen-2021-052554. PMID: 35882454Free PMC Article
Nishiyama K, Sanefuji M, Kurokawa M, Iwaya Y, Hamada N, Sonoda Y, Ogawa M, Shimono M, Suga R, Kusuhara K, Ohga S; Japan Environment and Children’s Study Group
Am J Kidney Dis 2022 Nov;80(5):619-628.e1. Epub 2022 Apr 16 doi: 10.1053/j.ajkd.2022.03.003. PMID: 35439592
Eshkoli T, Wainstock T, Sheiner E, Beharier O, Fraenkel M, Walfisch A
Am J Perinatol 2019 Jul;36(9):975-980. Epub 2018 Nov 26 doi: 10.1055/s-0038-1675834. PMID: 30477033
Bappal B, Raghupathy P, de Silva V, Khusaiby SM
Arch Dis Child Fetal Neonatal Ed 1999 May;80(3):F209-12. doi: 10.1136/fn.80.3.f209. PMID: 10212083Free PMC Article

Diagnosis

Hou AN, Wang Y, Pan YQ
J Clin Immunol 2023 Jul;43(5):979-988. Epub 2023 Mar 3 doi: 10.1007/s10875-023-01456-0. PMID: 36867340
Sarıkaya E, Kendirci M, Demir M, Dündar M
J Clin Res Pediatr Endocrinol 2023 Nov 22;15(4):426-430. Epub 2022 Apr 12 doi: 10.4274/jcrpe.galenos.2022.2021-12-19. PMID: 35410112Free PMC Article
Nishiyama K, Sanefuji M, Kurokawa M, Iwaya Y, Hamada N, Sonoda Y, Ogawa M, Shimono M, Suga R, Kusuhara K, Ohga S; Japan Environment and Children’s Study Group
Am J Kidney Dis 2022 Nov;80(5):619-628.e1. Epub 2022 Apr 16 doi: 10.1053/j.ajkd.2022.03.003. PMID: 35439592
London S, De Franco E, Elias-Assad G, Barhoum MN, Felszer C, Paniakov M, Weiner SA, Tenenbaum-Rakover Y
Front Endocrinol (Lausanne) 2021;12:673755. Epub 2021 May 18 doi: 10.3389/fendo.2021.673755. PMID: 34093443Free PMC Article
Muir AB, Rose SR
Clin Perinatol 2018 Mar;45(1):xvii-xviii. Epub 2017 Dec 1 doi: 10.1016/j.clp.2017.11.004. PMID: 29406016

Therapy

Hizkiyahu R, Badeghiesh A, Baghlaf H, Dahan MH
J Matern Fetal Neonatal Med 2023 Dec;36(2):2278027. Epub 2023 Nov 7 doi: 10.1080/14767058.2023.2278027. PMID: 37935517
Nikolaou M, Vasilakis IA, Marinakis NM, Tilemis FN, Zellos A, Lykopoulou E, Traeger-Synodinos J, Kanaka-Gantenbein C
Hormones (Athens) 2023 Sep;22(3):515-520. Epub 2023 Jul 26 doi: 10.1007/s42000-023-00468-0. PMID: 37493943
Gaisl O, Konrad D, Joset P, Lang-Muritano M
J Pediatr Endocrinol Metab 2019 Sep 25;32(9):1027-1030. doi: 10.1515/jpem-2019-0057. PMID: 31271559
Turunen S, Vääräsmäki M, Männistö T, Hartikainen AL, Lahesmaa-Korpinen AM, Gissler M, Suvanto E
Thyroid 2019 Jan;29(1):135-141. Epub 2018 Dec 20 doi: 10.1089/thy.2018.0311. PMID: 30417761
Muir AB, Rose SR
Clin Perinatol 2018 Mar;45(1):xvii-xviii. Epub 2017 Dec 1 doi: 10.1016/j.clp.2017.11.004. PMID: 29406016

Prognosis

Yap PPH, Papachristou Nadal I, Rysinova V, Basri NI, Samsudin IN, Forbes A, Noor NM, Supian ZA, Hassan H, Paimin F, Zakaria R, Mohamed Alias SR, Ismail Bukhary NB, Benton M, Ismail K, Chew BH
BMJ Open 2022 Jul 26;12(7):e052554. doi: 10.1136/bmjopen-2021-052554. PMID: 35882454Free PMC Article
London S, De Franco E, Elias-Assad G, Barhoum MN, Felszer C, Paniakov M, Weiner SA, Tenenbaum-Rakover Y
Front Endocrinol (Lausanne) 2021;12:673755. Epub 2021 May 18 doi: 10.3389/fendo.2021.673755. PMID: 34093443Free PMC Article
Splittstoesser V, Vollbach H, Plamper M, Garbe W, De Franco E, Houghton JAL, Dueker G, Ganschow R, Gohlke B, Schreiner F
Front Endocrinol (Lausanne) 2021;12:665336. Epub 2021 Apr 16 doi: 10.3389/fendo.2021.665336. PMID: 33935973Free PMC Article
Senée V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougnères P, Taha D, Julier C
Nat Genet 2006 Jun;38(6):682-7. Epub 2006 May 21 doi: 10.1038/ng1802. PMID: 16715098
Bappal B, Raghupathy P, de Silva V, Khusaiby SM
Arch Dis Child Fetal Neonatal Ed 1999 May;80(3):F209-12. doi: 10.1136/fn.80.3.f209. PMID: 10212083Free PMC Article

Clinical prediction guides

Hou AN, Wang Y, Pan YQ
J Clin Immunol 2023 Jul;43(5):979-988. Epub 2023 Mar 3 doi: 10.1007/s10875-023-01456-0. PMID: 36867340
Sarıkaya E, Kendirci M, Demir M, Dündar M
J Clin Res Pediatr Endocrinol 2023 Nov 22;15(4):426-430. Epub 2022 Apr 12 doi: 10.4274/jcrpe.galenos.2022.2021-12-19. PMID: 35410112Free PMC Article
Yap PPH, Papachristou Nadal I, Rysinova V, Basri NI, Samsudin IN, Forbes A, Noor NM, Supian ZA, Hassan H, Paimin F, Zakaria R, Mohamed Alias SR, Ismail Bukhary NB, Benton M, Ismail K, Chew BH
BMJ Open 2022 Jul 26;12(7):e052554. doi: 10.1136/bmjopen-2021-052554. PMID: 35882454Free PMC Article
Perdas E, Gadzalska K, Hrytsiuk I, Borowiec M, Fendler W, Młynarski W
Pediatr Diabetes 2022 Sep;23(6):668-674. Epub 2022 Apr 24 doi: 10.1111/pedi.13341. PMID: 35394098
London S, De Franco E, Elias-Assad G, Barhoum MN, Felszer C, Paniakov M, Weiner SA, Tenenbaum-Rakover Y
Front Endocrinol (Lausanne) 2021;12:673755. Epub 2021 May 18 doi: 10.3389/fendo.2021.673755. PMID: 34093443Free PMC Article

Recent systematic reviews

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