Devel. bio exam 3 sg cards.txt

The remodeling of primary capillary networks that creates veins and arteries. This requires capillary network.

Epithelial cells that respond to VEGFA during angiogenesis that sprout to form new vessels. Tip cells have filopodia that express high levels of FLK1 and VEGFR-3 that extend out toward VEGF signal that comes from developing embryonic organs and by endoderm.

It is involved in beginning angiogenesis and functions to prune, remodel, and allow for outgrowth of capillaries.

PDGFR and TGF-betaR are involved in the final steps of remodeling and connecting arteries and veins.

Tip cells express Notch and Notch blocks adjacent cells from responding to VEGFA

The blood vessels are created de novo from lateral plate mesoderm.

They become hemangioblasts per Cdx4

Notch decides if they become angioblasts or blood cells

Amniotes have 2 waves of vasculogenesis - yolk sac and intraembryonic.

bFGF or FGF3, VEGF (there are 5 different one), and agiopoietens.

VEGF acts through 3 receptors to recruit cells and form sheets and tubes (VEGF or VEGPR null mutant mice lack blood islands and do not undergo vasculogenesis)

It produces RBCs

Forms the dorsal aorta and vessels that connect with capillary networks that form in the mesoderm (only occurs in the embryo). Vasculogenesis is not associated with blood development. Intraembryonic vascular networks arise from individual angioblast progenitor cells and they DO NOT come from larger vessels. **Fgf2 necessary for the generation of hemangioblasts from the splanchnic mesoderm.**

They differ in oxygenated status of blood, muscularity of walls, and presence of valves. It is a closed system and must hook up correctly.

A strong Notch signal, gridlock and ephrin-B2 induce arteries. Small Notch signal induce angioblasts. EphB4 induces veins.

Tie2 and Ang1 are involved in smooth muscle formation.

Ventricular myocytes, atrial myocytes, endothelial lining of heart and valves, apicardium all derived from the same progenitor cells.

Where BMP, Fgf8, and Wnt coincide.

• What are the transcription factors that are crucial for heart development?
• GATA4 and Nkx2-5. GATA4 is turned on first, then Nkx2-5, then they form a positive feedback loop.

• Tbx5 is important for cardiac development and is initially expressed in the entire ventricular primordial heart field and later becomes restricted to the right atrium, left atrium, and left ventricle. This restriction of Tbx5 expression leads to right ventricle development in a 4 chambered heart. Tbx5 restriction is necessary for 4 chambers.
• Where do neural crest cells derive from?
• They come from the dorsal neural tube and then detach and undergo a transition to a mesenchymal form and detach from the neural tube.

The septa separates the truncus arteriosus into the pulmonary artery and aorta form from cells of the cardiac neural crest.

Cell death of aortic arches is necessary for normal aortic development.

Esophagotracheal fistulas

The trachea and esophagus

Branching morphogenesis involves growth from the center outward, like the way a tree grows. This means that the first bronchial branches form first. Subsequent branches produce more distal bronchial branches. The lung bud responds to left-right asymmetry cues including Tgfbeta-related molecules, such as activin receptor 3, Lefty1, Lefty3 and growth differentiation factor 1, and by the bicoid type homeobox gene Pitx2.

Humans have 2 left lobes and 3 right lobes. Mice have 1 left lobe and 4 right lobes.

TGFbeta/BMP and FGF signaling pathways

FGF

The terminal branches of the lungs and coordinated development of vasculature, smooth muscle, and differentiation of type II and type I alveolar cells is required.

They are cubiodal cells that can regenerate or form type 1 cells and produce surfactant.

Cells that flatten and enable greater gas exchange.

Production of surfactant is a key step in the transition to air breathing and forms a physical barrier between gas and liquid in the alveoli and reduces surface tension. It keeps aveoli from collapsing.

The esophagus, stomach, small intestine, and large intestine.

The endoderm. The endoderm only forms the lining of the tube. Cells from the splanchnic and lateral plate mesoderm will surround the tube and form the smooth muscle.

The esophagus, stomach, liver, pancreas, intestines, and cloaca.

Smooth muscle

Positive signaling from the cardiogenic mesoderm and inhibition by notochord, ectoderm, and mesenchyme.

In the 4th week, the liver, gallbladder, and biliary duct system

Between the layers of the ventral mesogastrium to give rise to the primordium of the liver.

Hepatocytes and epithelial lining of the intrahepatic duct.

The gallbladder and cystic duct.

The extrahepatic biliary duct (bile duct). The duct is occluded with epithelial cells and must undergo canalization to form functional ducts.

The pancreas develops from two buds from the gut tube, the ventral and dorsal pancreatic sections. These sections fuse to form the pancreas.

The ventral pancreatic bud rotates around clockwise to the dorsal pancreatic bud and fuses

At 5 weeks, the midgut is attached to the dorsal mesentery and communicates with the yolk sac via the vitelline (omphaloenteric) duct. It is supplied blood by the superior mesenteric artery. The midgut is divided into the cranial and caudal limbs based on attachment to vitelline duct.Rapid elongation of the cranial limb and its mesentery. Rotation of limbs along the axis of the superior mesenteric artery.Cuadal limb of midgut rotates to cranial position. A retraction of the herniated loops occurs in the 10th week in association with expansion of the abdominal cavity. The cecum is the last part of the gut to re-enter. It descends into the right iliac fossa. The distal end of the cecum forms the appendix, a narrow diverticulum, at this time. The ascending and descending colon and duodenum reattach to the dorsal abdominal wall (retroperitoneal) fixing the position of the organization of the intestines.

The duodenum and jujenum.

The ileum, cecum, appendix, ascending colon, and 2/3 of the transverse colon.

In the 5th week, the epithelium of the small intestines proliferate. Intestines are occluded by a solid plug by the 6th to 7th week.Through the process of recanalization, a secondary lumina appears. The mesoderm aggregates and pushes into the epithelium to form intestinal villi. Epithelium transforms into a simple columnar epithelium.

The hindgut ends with the cloacal membrane � composed of endoderm and ectoderm of anal pit (proctodeum). Cloaca is divided by urorectal septum. Urorectal septum grows toward the cloacal membrane through infolding of lateral cloacal wall. Septum ultimately leads to the separation of the cloaca into the rectum and cranial anal canal and the urogenital sinus.

Variations in the liver lobulation is common but not clinically significant. Accessory hepatic ducts and duplication of the gallbladder are also common and usually asymptomatic. Extrahepatic biliary atresia � blockage of the biliary tracy that occurs in 1 in 15,000 live births. This leads to jaundice � yellow coloration due to buildup of bile entering the blood.

Annular pancreas. The ventral pancreatic bud can form as two lobes with common duct. If the two lobes migrate in opposite directions around the duodenum, they can compress the duodenum and cause gastrointestinal obstruction.

Congenital omphalocele. Persistent herniation of abdominal contents with a proportionally smaller abdominal cavity. The hernia sac is covered by the epithelium of the umbilical cord.

abnormal development of the urorectal septum, Anorectal Agenesis, Anal stenosis, Membranous atresia of anus, A failure to the anal membrane to perforate at the end of the 8th week.

Anorectal defect. Can occur with or without a fistula. Most common type of anorectal defects.

The result of a narrow anus and anal canal. Believed to be caused by dorsal deviation of urorectal septum.

The result of a thin layer of tissue obstructing the anal canal.

Pre-kidneys that appear in the 4th week of development and are NOT functional

Pre-kidneys that appear late in the 4th week and functions for about 4 weeks.

develops between 5th and 15th weeks and becomes the functional kidney. A metanephric blastema develops from intermediate mesoderm on each side of the body axis early in the 5th week. Simultaneously, each mesonephric duct sprounts a uretic bud that grows into each metanephric blastema. By the 6th week, the ureteric bud bifurcates and the two growing tips (ampullae) induces cranial and caudal lobes in the metanephros. Additional lobules form during the next 10 weeks in response to further bifurcation of the ureteric buds.

They rotate and relocate.

Autosomal dominant polycystic kidney disease incidence of 1/400-1/1000. 85% of the patients having a mutation of the PKD1 gene. Mutations have also been found on related PKD2 and PKD3 genes. Cysta normally appear adults around 10 years of age. Polycystic kidney disease is associated with an abnormal rate of tubule divisions, with hypoplasia of portions of tubules left behind as the ureteral bud advances.

Unilateral renal agenesis occurs at an incidence rate of 1/1000. The remaining kidney undergoes compensatory hypertrophy, which leads to an asymptomatic condition. Bilateral renal agenesis occurs at an incidence rate of 1/3000.

At an incidence rate of 1/600, the kidneys fuse at the midline to form a horseshoe kidney. The fusion is believed to occur during the 5th week of development when the two developing kidneys lie very close to each other. Approx. 7% of persons with turner�s syndrome (XO) have horseshoe kidneys.

Need AMH and testosterone, which causes degeneration of the Mullerian duct. Testosterone induces Wolffian duct to differentiate into epididymis, vas deferens, and seminal vesicles and induces urogenital swellings to develop into the scrotum and penis.

The vas deferens, epididymis, and seminal vesicle.

The Mullerian ducts develop while Wolffian ducts degenerate. Mullerian duct differentiates into the oviduct, uterus, cervix, and upper portion of vagina. Paramesonephric ducts form and will become the fallopian tubes. Estrogen from mother and genital tract induced female phenotype in XO

The genital ridge.

The fusion of germ cells.

1) germ cells determined by autonomous cytoplasmic determinants (germ plasm) 2) Germ cells specified by inductive interactions between cells.

No

bone morphogenic proteins. The germ cells form at the junction of the extraembryonic ectoderm, epiblast, primitive streak, and allantois.

fragilis and stella

At e7 the cells leave the posterior primitive streak, and enter the endoderm. They enter the hindgut and migrate dorsally until e9. Then they exit the hindgut and stall, then at e10, they enter the genital ridges. E11.5 they enter the gonad. The population proliferates to 2500-5000 PGC during migration. In the gonad mitosis, the population continues to increase the number of PGCs.

SF-1, WT1, LHX9, WNT4, SOX9, FGF9, and GATA4 in both male and female creating a bipotential gonad.

Important to make males. SRY is the sex determining region of the y chromosome and has 223 amino acids. It contains a high mobility group box (HMG box) � therefore it is likely a transcription factor. SRY is a mammalian gene only. Sry is detected in XY and rare XX males, but absent from XX and XY females. There is evidence that SRY is testis determining factor.

In testis and in the somatic cells of indifferent gonad immediately before and during testis differentiation.

turns on SF-1 and FGF9 leading to male fate. SRY turns on Sox9. Autosomal HMG box protein, ma be a transcription factor. At time of sex determination Sox9 migrates into the nucleus and binds to AMH/AMF promoter. May also be a splicing factor � can replace missing splicing factors in experimental splicing assays. XX humans that have an extra copy of Sox9 develop as males even without SRY

Soluble protein, binds to receptor and activates Disheveled. Disheveled, part of the Wnt pathway increases active beta-catenin. Beta catenin acts in a positive feedback loop with Wnt4 and Rspo1. XX individuals with RSPO1 mutations are phenotypically male. RSPO1 is absolutely critical for development of ovary (and external genitalia)

Turns on Rspo1 and they turn on beta-catenin, which turns off Sox9 and leads to female fate. Expressed in the genital ridge at bipotential stage, and is maintained ony in XX gonads. Beta-catenin is activated and it initiates the ovary differentiation pathway. In Wnt4 -/- mice, the ovary does not form properly and cells express testis specific genes including AMH/AMF and testosterone.

Only stays on in females. In males 2 copies of Dax1 leads to gonadal dysgenesis - phenotypical female, male with internal, un-dropped testes, and are infertile. Dax1 is a member of nuclear hormone receptor family. Expressed in the male and female genital ridges initially. SRY and Dax1 expressed in same cells but eventually Dax1 is expressed solely in the XX gonadal ridge. Antagonizes function of SRY and Sox9 and down-regulated SF1 expression. This is why 2 copies of Dax1 will overcome SRY and Sox9. There is just too much Dax1 protein for Sry and Sox9 to do their jobs

Necessary for Leydig cells to proliferate. Promotes Sertoli cell differentiation and mesonephric cell migration necessary for testis cords to form.

Turned on in the absence of Sx1 and leads to male fate.

Allows mullerian ducts to develop while the Wolffian ducts degenerate in females.

In males AMH and testosterone is absolutely crucial. AMH causes degeneration of Mullerian duct. Testosterone induces Wolffian duct to differentiate into epididymis, vas deferens, and seminal vesicles and induces urogenital swelling to develop into the scrotum and penis.

Promoting development of male urethra, prostate, penis, and scrotum. Humans with a defect in 5 alpha reductase, lack the ability to convert testosterone into DHT. XY children that lack this enzyme are XY, they have functioning undescended testes, enlarged clitoris, and blind vaginal pouch and appear to be female. At puberty increased testosterone levels induce differentiation of external genitalia � penis enlarges and scrotum descends.

XY individuals that have SRY gene and have testes and make testosterone and AMH but lack testosterone receptor. Respond to estrogen made by adrenal glands and have female appearance but lack uterus and oviducts and have testes in the abdomen.

CYP19 gene is the aromatase gene. Exposure to atrazine turns off CYP19 which leads to increase of aromatase. Aromatase converts testosterone to estrogen, feminizing the animals.

Crepidula fornicate (slipper snails) pile up on each other, born male, and if attached to a female will become male. If they are removed from female attachment, they become female. Also if there is a large population of males, some will become female.

The dorsal neural tube and detach. Epithelial neural tube cells undergo a transition to a mesenchymal form and detach from the neural tube.

1) Neural crest migrates from the dorsal neural tube 2) Migration can be segmented specific in the cranial region 3) Migration is through rostral somites from ephrin signals 4) Neural crest is prepatterned 5) Neural crest is pluripotent and can differentiate into the types of tissues that ectoderm and mesoderm typically generate 6) Neural crest disorders are called neurocristopathies

Specifically through the rostral/anterior somites. Neural crest migration avoids ephrin proteins of the caudal/posterior sclerome.

Multiple cell types depending on genetic regulation

The pharyngeal region and hindbrain are highly segmented whereas segmentation is less evident in the forebrain and midbrain.

Considerable cranial migration of neural crest cells, paraxial mesoderm, and prechordal mesoderm.

Appear by the end of the 1st month. 4 lateral pairs of endodermally � lined outpocketings called pharyngeal pouches and an unpaired ventral midline diverticulum, the thyroid primordium. 4 pairs ectodermally covered inpocketing called pharyngeal grooves. Alternating with the pharyngeal grooves and pouches are paired masses of mesenchyme called pharyngeal arches. Central to each pharyngeal arch is prominent artery called an aortic arch, cartilage and nerve and skeletal muscle

Bone - Malleus, Incus, Meckel�s cartilage. Muscle � temporalis, masseter, mylohyoid

Bone - Stapes, styloid process, hyoid bone. Muscle � frontalis, buccinators, oris, oculi, occipitalis, platysma

Bone - hyoid bone. Muscle � stylopharyngeus

Bone- thyroid and cricoid cartilage. Muscle � pharyngeal muscles

Cleft lip results of a lack of fusion of maxillary and nasomedial processes. Bilateral cleft occurs when the entire premaxillary segment is searate from both maxillae. Premaxillar segment commonly protrudes past the normal facial contours. Caused by hypoplasia of the maxillary process

It develops the melanocytes, dorsal root ganglia, dermomyotome, chain ganglia, dorsal aorta, preaortic ganglia, enteric nervous system. The chain ganglia are laid down by neural crest cells that migrate from the closing neural tube.

Adult is just a larger version.

adult has some changes

complete metamorphosis from larva to adult form

Undifferentiated tissues within larval insects that are patterned to form adult tissues in holometabolous insects.

Growth of amputated body parts or nonfunctioning organs. The new tissue is considered to be identical to the previous tissue. Usually envisioned as the replacement of complex, multi-tissue structures. Requires de novo patterning of the tissue. Example � limbs/digits, tails/fins, liver

Regeneration that occurs through the repatterning of existing tissues with little new growth. Hydra are an example.

When differentiated cells divide while maintaining their differentiated functions. Zebrafish heart regenerates from cardiomyocytes. The cardiomyocytes are able to proliferate to form new heart muscle, unlike mammalian cardiomyocytes

dedifferentiation of adult structures to form an undifferentiated mass of cells that then can be respecified. Best studies example is Salamander limb regeneration. All of the cells are present in the new limb � skeletal muscle bone, cartilage, tendons, nerves, vascular, epidermis.

many differentiated cells have lost the ability to undergo cell division. The ability to regenerate by epimorphosis is dependent on thee cells retaining the ability to re-enter the cell cycle.

1) Epidermal cells adjacent to the stump migrate to cover the wound surface. Proloferation of hese cells will lead to the apical ectodermal cap (AEC). This is distinct from normal wound healing � no scar and dermis does not follow the epidermis. 2) The nerves degenerate at the site of the amputation. 3) Bone, cartilage, myocytes, and neurons dedifferentiate and become detached from one another. These cells migrate under the AEC t form the regeneration blastema. Differentiation gene transcription decreases. Mesenchyme proliferating gene transcription increases. 4) blastema cells redifferentiate to form the new structures of the limb.

has an apical ectodermal cap, like the AER, and cells that derive from dedifferentiation.

Yes, the limb bud has AER and progress zone in the mesenchyme. Regenerating limb has AEC and regeneration blastema in the mesenchyme. Limb regeneration is dependent on the interaction between mesenchyme and ectoderm. The progress zone can be replaces with regeneration blastema in the limb bud. The same patterning signals control both processes.

tissue specific adult stem cells serve as source of cells for regrowth. Several cell types have been identified in mammals that possess stem cell-like properties but are specified to one or a few cell fates. Satellite cells - skeletal muscle. Neural stem cells - neurons. Hematopoetic cells - blood cells, dendrytic cells, osteoclasts. Cardiac stem cells - cardimyocytes. Bulge cells - follicular cells and melanocytes

• act with specificity, they produce specificabnormalities at specific times during gestation. Specificity also applies to species, for example, aspirin and corticosteroids have been found to be teratogenic in mice and rats but appear to be safe in humans. They may have a dose-effect relationship. They must reach the developing embryo at a sufficient concentration to cause their effects.
• Potential mechanisms of teratogenic effects of ethanol ?
• Altered neural crest migration - ethanol treated neural crest cells prematurely initiate their differentiation into facial cartilage. Apoptosis of neurons - through the generation of ROS. Block the adhesive function of the L1 protein, similar to mutations in L1

was marketed as a sedative and given to pregnant women as an anti-nausea med. Children were born with flipper like limbs. Severity depended on the time and duration of exposure to the drug.

skunk cabbage. Sheep eat it� if they eat it when they are pregnant it causes severe neurological defects including cyclopia. Jervine and cyclopamine are made by the plant - jervine inhibits cholesterol synthesis and cyclopamine blocks SHH function. Sheep die at birth, lack pituitary and have severe brain defects.

third most prevalent form of mental retardation. Symptoms � mental retardation, small head, indistinct philtrum, narrow upper lip, brain abnormalities. Affects 1 out of every 500-750 births in the US.

characteristic set of defects absent or small jaws, cleft palate, aortic arch abnormalities, thymic deficiencies, abnormalities of CNS. Mechanism � alteration of Hox gene expression that results in altered anterior-posterior patterning. Cranial neural crest stop both migration and proliferation.

both are anti-seizure medications. Exposure in-utero carries 1% risk of neural tube defects (x10 normal risk).

an associates pattern of malformations, clinical features include cranial facial abnormalities, small mouth, cardiovascular defects, long fingers/toes, hyperconvex fingernails, and cleft lip

exogenous chemicals that interfere with the function of hormones, special class of teratogens. Mechanisms: 1) mimic - acts like a natural hormone 2) blockers - block the binding of a hormone to its receptor or blocks the synthesis of the hormone 3) triggers - bind to hormone receptors and elicits an abnormal response

synthetic estrogen. Prescribed in the 1930-70�s for women who had experienced miscarriages or premature deliveries. In 71 the FDA stopped it from being prescribed to pregnant women because it was linked to vaginal cancer in female offspring.

cervical hood, abnormally shaped cervix, adenosis, fallopian tube abnormalities, abnormally shaped uterus, higher rate of infertility, and increase risk for developing clear adenocarcinoma of the cervix and vagina.

causes defects in reproductive tract, abnormal genitalia, in mice exposure results in infertility, no clear in humans.

the 5� Hoxa cluster � Hoxa-9, a10, a11, and a13. Hox genes are homeotic genes that control development of structures along anteroposterior axis. They are organized into clusters on certain chromosomes.

vagina

cervix

Uterus

oviducts (fallopian tubes)

Wnt7a

Binds to estrogen receptor. The estrogen receptor in turn represses Wnt7a expression. A lack of Wnt7a misregulates Hox gene expression.

A xenoestrogen found in polycarbonate plastics, water, baby bottles, medical devices.

Mice exposed in utero to BPA levels consistant with human dietary levels had meiosis defects that resulted in aneuploides. Dysmorphology of sex organs, low sperm counts and behavioral changes associates with fetal exposure in animals.

• Competes with estradiol foe estrogen receptors in MCF7 breat cancer cells
• Viclozolin is?
• a dicarboximide non-systemic pestiside used to control fungi in vines, strawberries, veggie and fruits. It is an anti-adrenergic endocrine disruptor

1) Targets androgen receptor (AR) to nucleus. 2) In the presence of DHT-blocks androgen induces gene expression by blocking AR from binding to androgen response elements in the DNA 3) In the absence of DHT-induces AR to bind DNA and activate androgen responsive genes 4)This agonist/antagonist dual function poses serious risks for normal sexual differentiation and fertility in men exposed to vinclozolin.

Beyond the exposed generation. Vinclozolin exposed rate in f5 generation have stable epigenetic changes that are noted and disease rates are being observed that are similar to those exposed in utero. Children born to thalidomide exposed parents have 5x the rate of limb abnormalities.

Autosomal recessive disorder that occurs in all ethnic groups, but most common in northern European ancestory. Due to a deficiency in the enzyme phenylalanine hydroxylase (PAH). Phenylananine accumulates and is converted into phenylpyruvate. This buildup causes mental retardation, the severity of which is a spectrum. If untreated most cases are associated with an IQ under 30. Treatment � main treatment is a strict diet with very limited intake of phenylalanine (low protein). Avoid foods made with aspartame it releases phenylalanine when digested. Phenylalanine-free formula. Defects in 3 other enzymes can cause PKU. These enxymes are cofactors

An autosomal recessive trait. The baby appears normal at birth, but develops poor feeding and vomiting during 1st week of life. Lethargy and coma may follow soon. Hypoglycemia is common, and baby will die within a few weeks if undiagnosed.

These are branched chain hydrophobic amino acids. Deficiency of any degradative enzymes except transaminases results in acidosis. Decarboxylation of leucine, isoleacine and valine done by complex enzyme system �branched chain alpha ketoacid dehydrogenase that uses thiamine pyrophosphate (vit B1) as a coenzyme. Deficiency of alpha-ketoacid dehydrogenase causes MSUD named for sweet odor of urine.

Often first suspected due to peculiar odor of urine. Confirmed by amino acid analysis showing marked elevations of leucine, isoleucine and valine and alloisoleucine in the plasma or high levels of leucine, isoleucine and valine and their respective ketoacids in urine.

Causes children to age rapidly and die as early as 12, usually from heart failure or strokes. Babies appear normal in infancy but have profound growth failure during the 1st year. 90% of children with progeria have a mutation on the gene that encodes the protein lamina a. Splicing occurs abnormally, we get truncated lamin A protein. Dominant inheritance, but not genetic, so each child may be a sporadic mutation. The truncated protein lamin A causes nuclear morphological abnormalities, disorganization of heterochromatin, and defective repair of DNA damage and increased genomic instability. Characteristics � short stature, low weight, loss of subcutaneous fat, head large for face, prominent scalp veins, alopecia, delayed and abnormal dentition, stiff joints, no sexual maturation. These children DO NOT experience dementias.

Short term - dialysis clears the body fluids. Long term -diet low in branched chain amino acids with carefully added synthetic valine, leucine, and isoleucine. Prognosis - severe ketoacidosis, cerebral edema, and death may occur with stressful situation, infection, surgery. Mental and neurological deficits are common.

complex genetic disorder that primarily affects the nervous system caused by deletion of the maternal chromosome 15 or by paternal uniparental disomy. occurs when there is a problem with the maternal genes and the offspring only gets the paternal genes. Chracteristics � developmental delay, intellectual disability, sever speech impairment, and problems with movement and balance. Most affected children also have recurrent seizures and microcephaly. Usually have a happy, excitable demeanor, hyperactivity and short attention span, and difficulty sleeping and need less sleep than usual.

Occurs when there is a problem with the paternal genes and the offspring only get the maternal genes. So, caused by deletion in the paternal chromosome 15 or by maternal uniparental disomy. Characterized by hypotonia, feeding difficulties, poor growth, and delayed development. Affected individuals develop an insatiable appetite and chronic over-eating. They typically have mental retardation or learning disabilities and behavioral problems. Genitals in males and females are underdeveloped and usually infertile.