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Alacrima

MedGen UID:
87488
Concept ID:
C0344505
Disease or Syndrome
Synonyms: Alacrima (dry eye syndrome); Alacrima - hypolacrimation
SNOMED CT: Alacrima (253215004)
 
HPO: HP:0000522

Definition

Absence of tear secretion. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAlacrima

Conditions with this feature

Familial dysautonomia
MedGen UID:
41678
Concept ID:
C0013364
Disease or Syndrome
Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased.
Glucocorticoid deficiency with achalasia
MedGen UID:
82889
Concept ID:
C0271742
Disease or Syndrome
Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood glucose (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two.\n\nMany of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).\n\nPeople with this condition may have other neurological abnormalities, such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time.\n\nPeople with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.\n\nAlacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. They develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.
Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome
MedGen UID:
98032
Concept ID:
C0406709
Disease or Syndrome
The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.
PCWH syndrome
MedGen UID:
373160
Concept ID:
C1836727
Disease or Syndrome
PCWH syndrome is a complex neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy (see 118200), central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (see 142623) (Inoue et al., 2004). Inoue et al. (2004) proposed the acronym PCWH for this disorder.
Hereditary sensory and autonomic neuropathy type 1B
MedGen UID:
330880
Concept ID:
C1842586
Disease or Syndrome
The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN) in the absence of significant autonomic features, are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction. For a discussion of genetic heterogeneity of HSAN, see HSAN1A (162400).
Hyperuricemia, infantile, with abnormal behavior and normal hypoxanthine guanine phosphoribosyltransferase
MedGen UID:
383794
Concept ID:
C1855884
Disease or Syndrome
Syndromic X-linked intellectual disability 17
MedGen UID:
477091
Concept ID:
C3275460
Mental or Behavioral Dysfunction
Intellectual disability-alacrima-achalasia syndrome is a rare, genetic intellectual disability syndrome characterized by delayed motor and cognitive development, absence or severe delay in speech development, intellectual disability, and alacrima. Achalasia/dysphagia and mild autonomic dysfunction (i.e. anisocoria) have also been reported in some patients. The phenotype is similar to the one observed in autosomal recessive Triple A syndrome, but differs by the presence of intellectual disability in all affected individuals.
Hereditary sensory and autonomic neuropathy type 6
MedGen UID:
761278
Concept ID:
C3539003
Disease or Syndrome
Hereditary sensory and autonomic neuropathy type VI (HSAN6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection (summary by Edvardson et al., 2012). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).
Alacrima, congenital, autosomal recessive
MedGen UID:
861034
Concept ID:
C4012597
Disease or Syndrome
Glucocorticoid deficiency 2
MedGen UID:
891117
Concept ID:
C4049714
Disease or Syndrome
Familial glucocorticoid deficiency is an autosomal recessive disorder resulting from resistance to the action of adrenocorticotropin (ACTH) on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood (summary by Metherell et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of familial glucocorticoid deficiency, see GCCD1 (202200).
Alacrima, congenital, autosomal dominant
MedGen UID:
934803
Concept ID:
C4310836
Disease or Syndrome
Autosomal recessive limb-girdle muscular dystrophy type R18
MedGen UID:
1385598
Concept ID:
C4517996
Disease or Syndrome
Autosomal recessive limb-girdle muscular dystrophy-18 (LGMD18) is characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by Bogershausen et al., 2013). Additional more variable features include alacrima, achalasia, cataracts, or hepatic steatosis (Liang et al., 2015; Koehler et al., 2017). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
HELIX syndrome
MedGen UID:
1621482
Concept ID:
C4522164
Disease or Syndrome
HELIX syndrome is an autosomal recessive disorder characterized by Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia (summary by Hadj-Rabia et al., 2018).
Alacrima, achalasia, and intellectual disability syndrome
MedGen UID:
1640947
Concept ID:
C4706563
Disease or Syndrome
Alacrima, achalasia, and impaired intellectual development syndrome (AAMR) is an autosomal recessive disorder characterized by onset of these 3 main features at birth or in early infancy. More variable features include hypotonia, gait abnormalities, anisocoria, and visual or hearing deficits. The disorder shows similarity to the triple A syndrome (231550), but patients with AAMR do not have adrenal insufficiency (summary by Koehler et al., 2013). See also 300858 for a phenotypically similar disorder that shows X-linked inheritance.
Developmental and epileptic encephalopathy, 77
MedGen UID:
1684735
Concept ID:
C5231405
Disease or Syndrome
Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first months of life. Patients have severe global developmental delay, and may have additional variable features, including dysmorphic or coarse facial features, visual defects, and mild skeletal or renal anomalies. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Starr et al., 2019). For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Deeah syndrome
MedGen UID:
1756624
Concept ID:
C5436579
Disease or Syndrome
DEEAH syndrome is an autosomal recessive multisystemic disorder with onset in early infancy. Affected individuals usually present in the perinatal period with respiratory insufficiency, apneic episodes, and generalized hypotonia. The patients have failure to thrive and severely impaired global development with poor acquisition of motor, cognitive, and language skills. Other common features include endocrine, pancreatic exocrine, and autonomic dysfunction, as well as hematologic disturbances, mainly low hemoglobin. Patients also have dysmorphic and myopathic facial features. Additional more variable features include seizures, undescended testes, and distal skeletal anomalies. Death in early childhood may occur (summary by Schneeberger et al., 2020).
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia
MedGen UID:
1776912
Concept ID:
C5436585
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH) is an autosomal recessive disorder characterized by global developmental delay and mildly to severely impaired intellectual development with poor speech and language acquisition. Some patients may have early normal development with onset of the disorder in the first years of life. More variable neurologic abnormalities include hypotonia, seizures, apnea, mild signs of autonomic or peripheral neuropathy, and autism. Aside from dysmorphic facial features and occasional findings such as scoliosis or undescended testes, other organ systems are not involved (summary by Schneeberger et al., 2020).
Kilquist syndrome
MedGen UID:
1742639
Concept ID:
C5436756
Disease or Syndrome
Kilquist syndrome (KILQS) is an autosomal recessive multisystem disorder characterized by neurologic, gastrointestinal, and secretory dysfunction. Affected individuals present at birth with hypotonia, feeding difficulties, mild dysmorphic features, and sensorineural hearing loss. They show poor overall growth associated with gastrointestinal anomalies such as gastroesophageal reflux or midgut malrotation, as well as profound global developmental delay with inability to sit or speak. Tear, sweat, and saliva production is also impaired, causing dry mouth and recurrent bronchial mucus plugging. Some of the clinical features are reminiscent of cystic fibrosis (CF; 219700) (summary by Stodberg et al., 2020).
Otofaciocervical syndrome 2
MedGen UID:
1782278
Concept ID:
C5442121
Disease or Syndrome
Otofaciocervical syndrome-2 with T-cell deficiency (OTFCS2) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies including vertebral defects, low-set clavicles, winged scapulae, sloping shoulders, and mild intellectual disability (summary by Pohl et al., 2013). Patients have been reported who also exhibit altered thymus development with T-cell immunodeficiency and recurrent, sometimes fatal, infections (Paganini et al., 2017; Yamazaki et al., 2020). For a discussion of genetic heterogeneity of otofaciocervical syndrome, see OTFCS1 (166780).
Lacrimoauriculodentodigital syndrome 2
MedGen UID:
1824059
Concept ID:
C5774286
Disease or Syndrome
Lacrimoauriculodentodigital syndrome-2 (LADD2) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006).
Lacrimoauriculodentodigital syndrome 3
MedGen UID:
1824060
Concept ID:
C5774287
Disease or Syndrome
Lacrimoauriculodentodigital syndrome-3 (LADD3) is a multiple congenital anomaly disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies (summary by Milunsky et al., 2006).
LADD syndrome 1
MedGen UID:
1824096
Concept ID:
C5774323
Disease or Syndrome
Lacrimoauriculodentodigital syndrome-1 (LADD1) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006). Genetic Heterogeneity of Lacrimoauriculodentodigital Syndrome LADD syndrome-2 (LADD2; 620192) is caused by mutation in the FGFR3 gene (134934) on chromosome 4p16, and LADD syndrome-3 (LADD3; 620193) is caused by mutation in the FGF10 gene, an FGFR ligand, on chromosome 5p12.
Congenital disorder of deglycosylation 1
MedGen UID:
989503
Concept ID:
CN306977
Disease or Syndrome
Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.

Professional guidelines

PubMed

Zhang ZW, Guo X, Qi XP
Endocr Metab Immune Disord Drug Targets 2021;21(3):534-543. doi: 10.2174/1871530320666200910112230. PMID: 32914730
Rech ME, McCarthy JM, Chen CA, Edmond JC, Shah VS, Bosch DGM, Berry GT, Williams L, Madan-Khetarpal S, Niyazov D, Shaw-Smith C, Kovar EM, Lupo PJ, Schaaf CP
Am J Med Genet A 2020 Jun;182(6):1426-1437. Epub 2020 Apr 10 doi: 10.1002/ajmg.a.61580. PMID: 32275123
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Recent clinical studies

Etiology

Tong S, Ventola P, Frater CH, Klotz J, Phillips JM, Muppidi S, Dwight SS, Mueller WF, Beahm BJ, Wilsey M, Lee KJ
Hum Mol Genet 2023 Sep 5;32(18):2787-2796. doi: 10.1093/hmg/ddad106. PMID: 37379343Free PMC Article
Meyer A, Catto-Smith A, Crameri J, Simpson D, Alex G, Hardikar W, Cameron D, Oliver M
J Gastroenterol Hepatol 2017 Feb;32(2):395-400. doi: 10.1111/jgh.13484. PMID: 27411173
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Diagnosis

Zhao Z, Allen RC
Orbit 2022 Apr;41(2):162-169. Epub 2021 Sep 5 doi: 10.1080/01676830.2021.1974057. PMID: 34486478
Adams J, Schaaf CP
Clin Genet 2018 Jul;94(1):54-60. Epub 2018 Feb 5 doi: 10.1111/cge.13173. PMID: 29120068
Meyer A, Catto-Smith A, Crameri J, Simpson D, Alex G, Hardikar W, Cameron D, Oliver M
J Gastroenterol Hepatol 2017 Feb;32(2):395-400. doi: 10.1111/jgh.13484. PMID: 27411173
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Therapy

Asahina M, Fujinawa R, Hirayama H, Tozawa R, Kajii Y, Suzuki T
Mol Brain 2021 Jun 13;14(1):91. doi: 10.1186/s13041-021-00806-6. PMID: 34120625Free PMC Article
Jayant SS, Gupta R, Agrawal K, Das L, Dutta P, Bhansali A
Hormones (Athens) 2021 Mar;20(1):197-205. Epub 2020 Jul 22 doi: 10.1007/s42000-020-00217-7. PMID: 32700293
Li XX, Liu J, Chen YL, Chen GJ, Wang ZY, Zhu JJ, Guo YW, Wei XQ
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Meyer A, Catto-Smith A, Crameri J, Simpson D, Alex G, Hardikar W, Cameron D, Oliver M
J Gastroenterol Hepatol 2017 Feb;32(2):395-400. doi: 10.1111/jgh.13484. PMID: 27411173
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Prognosis

Tong S, Ventola P, Frater CH, Klotz J, Phillips JM, Muppidi S, Dwight SS, Mueller WF, Beahm BJ, Wilsey M, Lee KJ
Hum Mol Genet 2023 Sep 5;32(18):2787-2796. doi: 10.1093/hmg/ddad106. PMID: 37379343Free PMC Article
Stanclift CR, Dwight SS, Lee K, Eijkenboom QL, Wilsey M, Wilsey K, Kobayashi ES, Tong S, Bainbridge MN
Orphanet J Rare Dis 2022 Dec 17;17(1):440. doi: 10.1186/s13023-022-02592-3. PMID: 36528660Free PMC Article
Meyer A, Catto-Smith A, Crameri J, Simpson D, Alex G, Hardikar W, Cameron D, Oliver M
J Gastroenterol Hepatol 2017 Feb;32(2):395-400. doi: 10.1111/jgh.13484. PMID: 27411173
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Clinical prediction guides

Tong S, Ventola P, Frater CH, Klotz J, Phillips JM, Muppidi S, Dwight SS, Mueller WF, Beahm BJ, Wilsey M, Lee KJ
Hum Mol Genet 2023 Sep 5;32(18):2787-2796. doi: 10.1093/hmg/ddad106. PMID: 37379343Free PMC Article
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J Hum Genet 2020 Apr;65(4):387-396. Epub 2020 Jan 21 doi: 10.1038/s10038-019-0719-9. PMID: 31965062
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Recent systematic reviews

Zhang ZW, Guo X, Qi XP
Endocr Metab Immune Disord Drug Targets 2021;21(3):534-543. doi: 10.2174/1871530320666200910112230. PMID: 32914730

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