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LADD syndrome 1(LADD1)

MedGen UID:
1824096
Concept ID:
C5774323
Disease or Syndrome
Synonyms: FGFR2-Related Lacrimo-Auriculo-Dento-Digital Syndrome; Lacrimoauriculodentodigital syndrome 1; LADD1
 
Gene (location): FGFR2 (10q26.13)
 
Monarch Initiative: MONDO:0100302
OMIM®: 149730

Definition

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. [from OMIM]

Clinical features

From HPO
Nephrosclerosis
MedGen UID:
14330
Concept ID:
C0027719
Disease or Syndrome
Nephrosclerosis refers to thickening or scarring ("sclerosis") resulting from damage to the renal arterioles, also referred to as arteriosclerosis of the kidney arteries.
Renal agenesis
MedGen UID:
154237
Concept ID:
C0542519
Congenital Abnormality
Agenesis, that is, failure of the kidney to develop during embryogenesis and development.
Coronal hypospadias
MedGen UID:
234660
Concept ID:
C1394030
Congenital Abnormality
A mild form of hypospadias in which the urethra opens just under the corona glandis.
Triphalangeal thumb
MedGen UID:
66029
Concept ID:
C0241397
Congenital Abnormality
A thumb with three phalanges in a single, proximo-distal axis. Thus, this term applies if the thumb has an accessory phalanx, leading to a digit like appearance of the thumb.
Preaxial polydactyly
MedGen UID:
87498
Concept ID:
C0345354
Congenital Abnormality
A form of polydactyly in which the extra digit or digits are localized on the side of the thumb or great toe.
Short thumb
MedGen UID:
98469
Concept ID:
C0431890
Congenital Abnormality
Hypoplasia (congenital reduction in size) of the thumb.
2-3 finger cutaneous syndactyly
MedGen UID:
96573
Concept ID:
C0432055
Congenital Abnormality
A soft tissue continuity in the anteroposterior axis between the second to the third fingers that extends distally to at least the level of the proximal interphalangeal joints.
Hypoplasia of the radius
MedGen UID:
672334
Concept ID:
C0685381
Congenital Abnormality
Underdevelopment of the radius.
Absent radius
MedGen UID:
235613
Concept ID:
C1405984
Congenital Abnormality
Missing radius bone associated with congenital failure of development.
Small thenar eminence
MedGen UID:
335432
Concept ID:
C1846474
Finding
Underdevelopment of the thenar eminence with reduced palmar soft tissue mass surrounding the base of the thumb.
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
Hypoplasia of the ulna
MedGen UID:
395934
Concept ID:
C1860614
Congenital Abnormality
Underdevelopment of the ulna.
Broad hallux
MedGen UID:
401165
Concept ID:
C1867131
Finding
Visible increase in width of the hallux without an increase in the dorso-ventral dimension.
Absent proximal phalanx of thumb
MedGen UID:
867060
Concept ID:
C4021418
Finding
Absence of the proximal phalanx of the thumb. In contrast to the proximal phalanges of the digits 2-5, the proximal phalanx of the thumb is embryologically equivalent to the middle phalanges of the other digits, whereas the first metacarpal is embryologically of phalangeal origin and as such equivalent to the proximal phalanges of the other digits.
Bilateral triphalangeal thumbs
MedGen UID:
867267
Concept ID:
C4021627
Congenital Abnormality
A bilateral form of triphalangeal thumb.
Radial deviation of the 3rd finger
MedGen UID:
869914
Concept ID:
C4024345
Anatomical Abnormality
Displacement of the 3rd finger towards the radial side (i.e., towards the thumb).
Partial duplication of thumb phalanx
MedGen UID:
909031
Concept ID:
C4082168
Anatomical Abnormality
A partial duplication, depending on severity leading to a broad or bifid appearance, affecting one or more of the phalanges of the thumb. As opposed to a complete duplication there is still a variable degree of fusion between the duplicated bones.
Microtia
MedGen UID:
57535
Concept ID:
C0152423
Congenital Abnormality
Underdevelopment of the external ear.
Mixed hearing impairment
MedGen UID:
102336
Concept ID:
C0155552
Disease or Syndrome
A type of hearing loss resulting from a combination of conductive hearing impairment and sensorineural hearing impairment.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Cupped ear
MedGen UID:
335186
Concept ID:
C1845447
Congenital Abnormality
Laterally protruding ear that lacks antihelical folding (including absence of inferior and superior crura).
Conjunctivitis
MedGen UID:
1093
Concept ID:
C0009763
Disease or Syndrome
Inflammation of the conjunctiva.
Dacryocystitis
MedGen UID:
3686
Concept ID:
C0010930
Disease or Syndrome
Inflammation of the nasolacrimal sac.
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
Enamel hypoplasia
MedGen UID:
3730
Concept ID:
C0011351
Disease or Syndrome
Developmental hypoplasia of the dental enamel.
Partial congenital absence of teeth
MedGen UID:
43794
Concept ID:
C0020608
Congenital Abnormality
Tooth agenesis in some form is a common human anomaly that affects approximately 20% of the population. Although tooth agenesis is associated with numerous syndromes, several case reports describe nonsyndromic forms that are either sporadic or familial in nature, as reviewed by Gorlin et al. (1990). The incidence of familial tooth agenesis varies with each class of teeth. Most commonly affected are third molars (wisdom teeth), followed by either upper lateral incisors or lower second premolars; agenesis involving first and second molars is very rare. Also see 114600 and 302400. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). Faulty use of the terms, however, have confounded their use. The term 'partial anodontia' is obsolete (Salinas, 1978). Genetic Heterogeneity of Selective Tooth Agenesis Other forms of selective tooth agenesis include STHAG2 (602639), mapped to chromosome 16q12; STHAG3 (604625), caused by mutation in the PAX9 gene (167416) on chromosome 14q12; STHAG4 (150400), caused by mutation in the WNT10A gene (606268) on chromosome 2q35; STHAG5 (610926), mapped to chromosome 10q11; STHAG7 (616724), caused by mutation in the LRP6 gene (603507) on chromosome 12p13; STHAG8 (617073), caused by mutation in the WNT10B gene (601906) on chromosome 12q13; STHAG9 (617275), caused by mutation in the GREM2 gene (608832) on chromosome 1q43; STHAG10 (620173), caused by mutation in the TSPEAR gene (612920) on chromosome 21q22; and STHAGX1 (313500), caused by mutation in the EDA gene (300451) on chromosome Xq13. A type of selective tooth agenesis that was formerly designated STHAG6 has been incorporated into the dental anomalies and short stature syndrome (DASS; 601216). Of 34 unrelated patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) found that 56% (19 patients) had mutations in the WNT10A gene (STHAG4), whereas only 3% and 9% had mutations in the MSX1 (STHAG1) and PAX9 (STHAG3) genes, respectively. The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia. Genotype-Phenotype Correlations Yu et al. (2016) observed that the most frequently missing permanent teeth in WNT10B-associated oligodontia were the lateral incisors (83.3%), whereas premolars were missing only 51.4% of the time, which they noted was a pattern 'clearly different' from the oligodontia patterns resulting from WNT10A mutations. They also stated that the selective pattern in WNT10B mutants was different from that associated with mutations in other genes, such as MSX1, in which second premolars are missing, and PAX9, in which there is agenesis of molars.
Xerostomia
MedGen UID:
22735
Concept ID:
C0043352
Disease or Syndrome
Dryness of the mouth due to salivary gland dysfunction.
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
Microdontia
MedGen UID:
66008
Concept ID:
C0240340
Congenital Abnormality
Decreased size of the teeth, which can be defined as a mesiodistal tooth diameter (width) more than 2 SD below mean. Alternatively, an apparently decreased maximum width of tooth.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Nasolacrimal duct obstruction
MedGen UID:
226915
Concept ID:
C1281931
Finding
Blockage of the lacrimal duct.
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Delayed eruption of primary teeth
MedGen UID:
341477
Concept ID:
C1849538
Finding
Delayed tooth eruption affecting the primary dentition.
Conical incisor
MedGen UID:
341076
Concept ID:
C1856136
Finding
An abnormal conical morphology of the incisor tooth.
Absence of Stensen duct
MedGen UID:
347668
Concept ID:
C1858569
Finding
Lacrimal gland hypoplasia
MedGen UID:
350109
Concept ID:
C1863200
Finding
Underdevelopment of the lacrimal gland.
Absent lacrimal punctum
MedGen UID:
356683
Concept ID:
C1867060
Disease or Syndrome
No identifiable superior and/or inferior lacrimal punctum.
Hypoplastic lacrimal duct
MedGen UID:
368837
Concept ID:
C1968574
Finding
Hypoplasia of the lacrimal punctum
MedGen UID:
867206
Concept ID:
C4021564
Anatomical Abnormality
Underdevelopment of the lacrimal puncta.
Aplasia of the parotid gland
MedGen UID:
893144
Concept ID:
C4024215
Anatomical Abnormality
Absence of the parotid gland.
Lacrimal gland aplasia
MedGen UID:
870377
Concept ID:
C4024822
Finding
A congenital defect of development characterized by absence of the lacrimal gland.
Periorbital fullness
MedGen UID:
1710990
Concept ID:
C4760994
Finding
Increase in periorbital soft tissue.
Hyperextensible skin
MedGen UID:
66023
Concept ID:
C0241074
Finding
A condition in which the skin can be stretched beyond normal, and then returns to its initial position.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Recurrent corneal erosions
MedGen UID:
56353
Concept ID:
C0155119
Disease or Syndrome
The presence of recurrent corneal epithelial erosions. Although most corneal epithelial defects heal quickly, some may show recurrent ulcerations.
Corneal perforation
MedGen UID:
137914
Concept ID:
C0339293
Injury or Poisoning
A rupture of the cornea through which a portion of the iris protrudes.
Alacrima
MedGen UID:
87488
Concept ID:
C0344505
Disease or Syndrome
Absence of tear secretion.
Limbal stem cell deficiency
MedGen UID:
295775
Concept ID:
C1561989
Disease or Syndrome
A condition characterized by a loss or deficiency of the stem cells in the limbus that are vital for re-population of the corneal epithelium and to the barrier function of the limbus.

Term Hierarchy

Professional guidelines

PubMed

Martinez SA, Fligor SC, Tsikis S, Short M, Corcoran KE, Rogers A, Gura KM, Puder M
Orphanet J Rare Dis 2023 May 11;18(1):113. doi: 10.1186/s13023-023-02722-5. PMID: 37170358Free PMC Article
Svetanoff WJ, Srivatsa S, Diefenbach K, Nwomeh BC
Semin Pediatr Surg 2022 Feb;31(1):151141. Epub 2022 Feb 18 doi: 10.1016/j.sempedsurg.2022.151141. PMID: 35305800
Hand Surgery Quality Consortium, Zhuang T, Shapiro LM, Ring D, Akelman E, Ruch DS, Richard MJ, Ladd A, Blazar P, Yao J, Kakar S, Harris AHS, Got C, Kamal RN
J Hand Surg Am 2020 Aug;45(8):690-697.e7. Epub 2020 Apr 25 doi: 10.1016/j.jhsa.2020.03.008. PMID: 32340760

Recent clinical studies

Etiology

Svetanoff WJ, Srivatsa S, Diefenbach K, Nwomeh BC
Semin Pediatr Surg 2022 Feb;31(1):151141. Epub 2022 Feb 18 doi: 10.1016/j.sempedsurg.2022.151141. PMID: 35305800
STARSurg Collaborative and COVIDSurg Collaborative
Br J Surg 2021 Dec 1;108(12):1448-1464. doi: 10.1093/bjs/znab336. PMID: 34871379Free PMC Article
Ryerson LM, Pharis S, Pockett C, Soni R, Fruitman D, Guleserian KJ, Nater M, Raynor SC, Mackie AS, Dicken B
Pediatrics 2018 Aug;142(2) doi: 10.1542/peds.2017-4267. PMID: 30049892
Landisch R, Abdel-Hafeez AH, Massoumi R, Christensen M, Shillingford A, Wagner AJ
J Pediatr Surg 2015 Nov;50(11):1971-4. Epub 2015 Aug 8 doi: 10.1016/j.jpedsurg.2015.08.002. PMID: 26358665
Salavitabar A, Anderson BR, Aspelund G, Starc TJ, Lai WW
J Pediatr Surg 2015 Oct;50(10):1695-700. Epub 2015 Mar 7 doi: 10.1016/j.jpedsurg.2015.02.065. PMID: 25783348

Diagnosis

Svetanoff WJ, Srivatsa S, Diefenbach K, Nwomeh BC
Semin Pediatr Surg 2022 Feb;31(1):151141. Epub 2022 Feb 18 doi: 10.1016/j.sempedsurg.2022.151141. PMID: 35305800
STARSurg Collaborative and COVIDSurg Collaborative
Br J Surg 2021 Dec 1;108(12):1448-1464. doi: 10.1093/bjs/znab336. PMID: 34871379Free PMC Article
Ryerson LM, Pharis S, Pockett C, Soni R, Fruitman D, Guleserian KJ, Nater M, Raynor SC, Mackie AS, Dicken B
Pediatrics 2018 Aug;142(2) doi: 10.1542/peds.2017-4267. PMID: 30049892
Yokote K, Chanprasert S, Lee L, Eirich K, Takemoto M, Watanabe A, Koizumi N, Lessel D, Mori T, Hisama FM, Ladd PD, Angle B, Baris H, Cefle K, Palanduz S, Ozturk S, Chateau A, Deguchi K, Easwar TK, Federico A, Fox A, Grebe TA, Hay B, Nampoothiri S, Seiter K, Streeten E, Piña-Aguilar RE, Poke G, Poot M, Posmyk R, Martin GM, Kubisch C, Schindler D, Oshima J
Hum Mutat 2017 Jan;38(1):7-15. Epub 2016 Oct 7 doi: 10.1002/humu.23128. PMID: 27667302Free PMC Article
Landisch R, Abdel-Hafeez AH, Massoumi R, Christensen M, Shillingford A, Wagner AJ
J Pediatr Surg 2015 Nov;50(11):1971-4. Epub 2015 Aug 8 doi: 10.1016/j.jpedsurg.2015.08.002. PMID: 26358665

Therapy

NIHR Global Health Research Unit on Global Surgery; STARSurg Collaborative
Lancet Digit Health 2024 Jul;6(7):e507-e519. doi: 10.1016/S2589-7500(24)00065-7. PMID: 38906616
Lim SY, Lee J, Osuna CE, Vikhe P, Schalk DR, Chen E, Fray E, Kumar M, Schultz-Darken N, Rakasz E, Capuano S, Ladd RA, Gil HM, Evans DT, Jeng EK, Seaman M, Martin M, Van Dorp C, Perelson AS, Wong HC, Siliciano JD, Siliciano R, Safrit JT, Nixon DF, Soon-Shiong P, Nussenzweig M, Whitney JB
Science 2024 Mar 8;383(6687):1104-1111. Epub 2024 Feb 29 doi: 10.1126/science.adf7966. PMID: 38422185Free PMC Article
Hart PA, Osypchuk Y, Hovbakh I, Shah RJ, Nieto J, Cote GA, Avgaitis S, Kremzer O, Buxbaum J, Inamdar S, Fass R, Phillips RW, Yadav D, Ladd AM, Al-Assi MT, Gardner T, Conwell DL, Irani S, Sheikh A, Nuttall J; TACTIC Study Investigators
Gastroenterology 2024 Apr;166(4):658-666.e6. Epub 2023 Dec 15 doi: 10.1053/j.gastro.2023.12.008. PMID: 38103842
Ryerson LM, Pharis S, Pockett C, Soni R, Fruitman D, Guleserian KJ, Nater M, Raynor SC, Mackie AS, Dicken B
Pediatrics 2018 Aug;142(2) doi: 10.1542/peds.2017-4267. PMID: 30049892
Reese D, Henning JS, Rockers K, Ladd D, Gilson R
Cutis 2011 Jan;87(1):24-9. PMID: 21323097

Prognosis

Ryerson LM, Pharis S, Pockett C, Soni R, Fruitman D, Guleserian KJ, Nater M, Raynor SC, Mackie AS, Dicken B
Pediatrics 2018 Aug;142(2) doi: 10.1542/peds.2017-4267. PMID: 30049892
Landisch RM, Loomba RS, Salazar JH, Buelow MW, Frommelt M, Anderson RH, Wagner AJ
J Pediatr Surg 2018 Jun;53(6):1118-1122. Epub 2018 Mar 6 doi: 10.1016/j.jpedsurg.2018.02.071. PMID: 29605269
Landisch R, Abdel-Hafeez AH, Massoumi R, Christensen M, Shillingford A, Wagner AJ
J Pediatr Surg 2015 Nov;50(11):1971-4. Epub 2015 Aug 8 doi: 10.1016/j.jpedsurg.2015.08.002. PMID: 26358665
Salavitabar A, Anderson BR, Aspelund G, Starc TJ, Lai WW
J Pediatr Surg 2015 Oct;50(10):1695-700. Epub 2015 Mar 7 doi: 10.1016/j.jpedsurg.2015.02.065. PMID: 25783348
Escobar MA, Ladd AP, Grosfeld JL, West KW, Rescorla FJ, Scherer LR 3rd, Engum SA, Rouse TM, Billmire DF
J Pediatr Surg 2004 Jun;39(6):867-71; discussion 867-71. doi: 10.1016/j.jpedsurg.2004.02.025. PMID: 15185215

Clinical prediction guides

Hart PA, Osypchuk Y, Hovbakh I, Shah RJ, Nieto J, Cote GA, Avgaitis S, Kremzer O, Buxbaum J, Inamdar S, Fass R, Phillips RW, Yadav D, Ladd AM, Al-Assi MT, Gardner T, Conwell DL, Irani S, Sheikh A, Nuttall J; TACTIC Study Investigators
Gastroenterology 2024 Apr;166(4):658-666.e6. Epub 2023 Dec 15 doi: 10.1053/j.gastro.2023.12.008. PMID: 38103842
Zhu H, Yu GY
J Stomatol Oral Maxillofac Surg 2022 Nov;123(6):e988-e990. Epub 2022 Jul 21 doi: 10.1016/j.jormas.2022.07.014. PMID: 35870793
Glasbey JC, Nepogodiev D, Simoes JFF, Omar O, Li E, Venn ML, Pgdme, Abou Chaar MK, Capizzi V, Chaudhry D, Desai A, Edwards JG, Evans JP, Fiore M, Videria JF, Ford SJ, Ganly I, Griffiths EA, Gujjuri RR, Kolias AG, Kaafarani HMA, Minaya-Bravo A, McKay SC, Mohan HM, Roberts KJ, San Miguel-Méndez C, Pockney P, Shaw R, Smart NJ, Stewart GD, Sundar Mrcog S, Vidya R, Bhangu AA; COVIDSurg Collaborative
J Clin Oncol 2021 Jan 1;39(1):66-78. Epub 2020 Oct 6 doi: 10.1200/JCO.20.01933. PMID: 33021869Free PMC Article
Ryerson LM, Pharis S, Pockett C, Soni R, Fruitman D, Guleserian KJ, Nater M, Raynor SC, Mackie AS, Dicken B
Pediatrics 2018 Aug;142(2) doi: 10.1542/peds.2017-4267. PMID: 30049892
Landisch R, Abdel-Hafeez AH, Massoumi R, Christensen M, Shillingford A, Wagner AJ
J Pediatr Surg 2015 Nov;50(11):1971-4. Epub 2015 Aug 8 doi: 10.1016/j.jpedsurg.2015.08.002. PMID: 26358665

Recent systematic reviews

Cullis PS, Siminas S, Losty PD
Ann Surg 2016 Dec;264(6):1156-1161. doi: 10.1097/SLA.0000000000001563. PMID: 26704743
Landisch R, Abdel-Hafeez AH, Massoumi R, Christensen M, Shillingford A, Wagner AJ
J Pediatr Surg 2015 Nov;50(11):1971-4. Epub 2015 Aug 8 doi: 10.1016/j.jpedsurg.2015.08.002. PMID: 26358665

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